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“Repurposing Fenbendazole in Oncology: Hype vs. Hope in the Context of the ‘Joe Tippens Protocol'”

by with No Comment Research

20 July 2025

Category: Drug Repurposing & Experimental Therapies I

Oncology Trends & Public Perception

Medically Reviewed By: Dr. Htet Wai Moe (MBBS, MD-Pharmacology, PhD-Pharmacology)

Defence Services Medical Research Centre, Naypyitaw, Myanmar

Fenbendazole is a benzimidazole-class drug from the anthelmintic group, developed in the 1970s by the company Hoechst AG, now part of the Merck Group. It was initially created to treat parasitic worm infections in animals. Its mechanism involves the disruption of microtubule formation by binding to tubulin, a protein essential for cell division in parasites. Generally, it is considered safe for use in animals, even with long-term administration, and is approved by many regulatory bodies as a veterinary medicine. However, its use in humans is not approved in any country. Some researchers have explored its mechanism of disrupting microtubule formation to investigate its potential anticancer effects in animal studies, and to some extent, it has shown anticancer properties, but no clinical trial has confirmed this claim.

Around 2016, the survival story of an American cancer patient sparked a debate over whether Fenbendazole could completely cure any type of cancer. To support his claim, he shared a unique regimen that included Fenbendazole, which he had taken alongside his chemotherapy. This regimen went viral on the internet and became widely recognized as the “Joe Tippens Protocol.” Many cancer patients, especially those who had given up on standard treatment options, began following this protocol. However, the FDA, EMA, and the American Cancer Society have warned patients against using this approach, citing the lack of clinical trial data, unknown long-term side effects, and the risk of delaying proven standard cancer therapies.

What is the Joe Tippens Protocol?

Joe Tippens is an American cancer patient who was diagnosed with small cell lung cancer in 2016, a very aggressive form of cancer that had already metastasized to other organs like the bones and brain. His doctor gave him a grim prognosis, with just three months to live. While his standard chemotherapy was ongoing, Joe came across a research study from Oklahoma State University that involved Fenbendazole. The study was conducted on mice with glioblastoma, and Fenbendazole had shown anti-cancer activity in the lab. Adding to this hope, he also learned about a veterinarian who had used Fenbendazole to treat her cancer successfully. Encouraged by these anecdotal cases, Joe Tippens decided to add Fenbendazole to his standard treatment plan and created a combination regimen of Fenbendazole, vitamins, and natural medicine on his own. This combination of drugs and supplements later became popularized as the ‘Joe Tippens Protocol.’ As per anecdotal reports, such as those popularized by Joe Tippens, describe the use of Fenbendazole combined with various dietary supplements in his so-called Joe Tippens protocol. After three months of following this regimen, Joe Tippens claimed that his PET scan showed no evidence of cancer and that he was completely cancer-free. Interestingly, Joe Tippens was also a participant in a clinical trial for a novel anti-cancer drug at the time he used Fenbendazole, and he was reportedly the only patient out of 1,100 participants who was cured of cancer.

What Exactly Is the Mechanism of Action of Fenbendazole?

Fenbendazole, also known by its chemical name methyl N-(6-phenylsulfanyl-1H-benzimidazole-2-yl), is a benzimidazole anthelmintic primarily used to treat parasitic worm infections in animals. Fenbendazole is thought to act via disruption of microtubule function, which is essential for cell division and intracellular transport. Fenbendazole selectively binds to β-tubulin, a structural protein needed to form microtubules, and prevents the polymerization of microtubules. This disrupts the mitotic spindle, inhibiting cell division during metaphase. In parasites, this microtubule disruption also affects glucose uptake and intracellular transport, leading to energy depletion. As a result, the parasite is unable to generate ATP and dies due to starvation.

Some researchers believed that cancer cells, like parasites, heavily rely on microtubules for rapid division. By disrupting tubulin function, Fenbendazole may inhibit cancer cell proliferation, induce apoptosis (programmed cell death), and interfere with angiogenesis (formation of blood vessels in tumors). However, these effects are only observed in preclinical settings, and no human trials have been performed to verify this action.

Evidence from Preclinical Studies

Fenbendazole is extensively studied in preclinical studies on various cancer types. Preclinical results have shown mixed results, some promising tumor suppression (e.g., cervical cancer, NSCLC), but also failures in certain models (lymphoma, ovarian cancer unless bioavailability is improved). Bioavailability is found to be a consistent limitation. The preclinical study results are presented below in tabular form:

Animal Model/Cell lines

Journal/Year

Outcome

Mouse lymphoma (syngeneic)

Curr. Issue Mol Bio 2023

 

No tumor suppression, possible immune disruption

Cervical cancer (HeLa xenograft)

MDPI – Molecules (2025)

potent suppression of xenograft tumor growth, 100% survival in Fenbendazole-treated mice

NSCLC (A549 xenograft)

Scientific Reports (2018)

Fenbendazole treatment caused a partial alteration of the microtubule network

Liver cancer (H4IIE cells)

Biol. Pharm. Bull. (2022)

Cell cycle arrest, selective apoptosis

Ovarian cancer (in vivo)

PMC Article (2023)

Decreased cell proliferation in EOC cell line; in cell line xenograft mouse models, no effect on oral administration

Micelle formulation

Pharmaceutics (2020)

Improved bioavailability, No Severe toxicity

Evidence from Off-Label Fenbendazole Use in Human Case Studies

As of now, no controlled clinical trials have been conducted to evaluate the safety or efficacy of Fenbendazole in cancer patients, and robust clinical data are completely absent. However, a limited number of case reports and small case series have documented instances where patients self-administered Fenbendazole off-label alongside conventional or alternative therapies. While these anecdotal accounts offer insights into individual experiences. A summary of such reports is presented below in tabular form.

Case

Cancer Type

Fenbendazole Use & Co-Therapies’

Outcome

Safety

Case series (3 patients), 2025

Breast / Prostate / Melanoma

Fenbendazole + other therapies (no chemo)

Two Complete Remission (CR) achieved, one near‑CR

No adverse effects

80-year-old NSCLC patient

NSCLC

Self‑administered Fenbendazole (inspired by social media)

No tumor shrinking

Severe liver injury (resolved)

67‑yr patient with drug-induced liver injury

H/O-Colon cancer Premalignant skin lesion

Self‑administered Fenbendazole

Not specified

Severe liver injury (resolved)

Stage III rectal carcinoma

Rectal cancer

Fenbendazole + curcumin + vitamin D + CBD Oil

Tumor “scab” and lymph nodes shrank

No side effects reported

A few well-documented unusual responses (e.g., complete remissions) suggest that Fenbendazole could have biological activity in some contexts, but considering it as evidence is questionable. In any case, none of the reports include controlled conditions or comparable cohorts, and most involve concomitant therapies. No randomized or phase I–II trials exist to establish safety, dosing, or effectiveness.

Limitations of the use of Fenbendazole as an anticancer

  • Absence of clinical trial data
  • Drug interactions and potential toxicity, like severe liver injury
  • Issues with sourcing veterinary drugs for human use (No FDA or EMA approval for Human use)
  • Risk of delaying standard treatment

Possible contamination: Veterinary formulations are not subject to the same rigorous manufacturing standards as human medicines and may contain impurities, variable dosing, or excipients unsuitable for human consumption. Potential contamination further limits their applicability.

Pharmacokinetic concerns: Another significant concern of considering Fenbendazole is its poor oral bioavailability. Fenbendazole is developed for veterinary use, and it is never optimized for absorption in humans.

Conclusion

Fenbendazole is a humble veterinary anthelmintic drug that has suddenly come into the limelight as a potential treatment for cancer, mainly due to some anecdotal reports that surfaced among them. one of which was the Joe Tippens Protocol. Joe Tippens’s story on social media sparked a debate, and desperate cancer patients didn’t take a second thought before trying this veterinary product. However, while some might have benefitted, many have experienced serious side effects with no efficacy. Those who did benefit from Fenbendazole still have questionable causality, as they were also on standard therapy.

Another reason for Fenbendazole’s association with anticancer effects is its mechanism of action. Fenbendazole has demonstrated probable anticancer activity in preclinical settings through microtubule destabilization, cell cycle arrest, and apoptosis induction, along with selective cytotoxicity in proliferating cancer cells. Several animal studies and in vitro models have supported its tumor-suppressive potential, specifically in lung and cervical cancer models.

However, preclinical studies have not yet extended to clinical studies. No controlled human trials have been conducted, and the current knowledge about Fenbendazole’s anticancer effects is limited to some case reports and anecdotal experiences, many of which are complicated by concurrent standard therapies and a lack of robust clinical validation. Moreover, serious pharmacokinetic challenges, such as low oral bioavailability, further weaken its potential as a reliable human therapy in its current form.

In summary, while Fenbendazole presents itself as an interesting case for drug repurposing, the current evidence is insufficient, inconsistent, and mainly anecdotal. As of now, Fenbendazole remains a molecule of curiosity rather than clinical conviction. Until high-quality human trials are conducted to clarify its safety, dosing, and efficacy, Fenbendazole should not be considered a substitute for evidence-based cancer therapies.

Given its mechanism of action targeting cell division, which is fundamental to cancer progression, and the emergence of anecdotal reports, Fenbendazole has attracted some scientific curiosity. However, it remains an experimental drug with no evidence of efficacy in humans. In the absence of robust clinical trials, validated formulations, a defined safety profile, and regulatory approval, its use in cancer treatment should be approached with caution or avoided. At this stage, Fenbendazole represents a subject of investigation rather than a validated therapeutic option.

References

Blog of Joe Tippen, Updated 24 March 2022, https://mycancerstory.rocks/the-blog/

Dogra N, Madan E, Dey KK, Kundu R, Kumar M, Basu A, et al. Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways. Sci Rep. 2018;8:11926. doi: 10.1038/s41598-018-30158-6

Nguyen J, Nguyen TQ, Han B, Hoang BX. Oral Fenbendazole for cancer therapy in humans and animals. Anticancer Res. 2024; 44:3725–35. doi:10.21873/anticanres.17197.

William Makis, Ilyes Baghli, Pierrick Martinez; Fenbendazole as an Anticancer Agent? A Case Series of Self-Administration in Three Patients. Case Rep Oncol1 January 2025; 18 (1): 856–863. https://doi.org/10.1159/000546362

Yamaguchi T, Shimizu J, Oya Y, Horio Y, Hida T. Drug-Induced Liver Injury in a Patient with Nonsmall Cell Lung Cancer after the Self-Administration of Fenbendazole Based on Social Media Information. Case Rep Oncol. 2021 Jun 17;14(2):886-891. Doi: 10.1159/000516276. PMID: 34248555; PMCID: PMC8255718.

Case Report: Rectal Carcinoma Stage 3, Male, Aged 72, Fenbendazole.org, https://www.Fenbendazole.org/rectal-carcinoma-stage-3/

Lei, X.; Wang, Y.; Chen, Y.; Duan, J.; Gao, X.; Cong, Z. Fenbendazole Exhibits Antitumor Activity Against Cervical Cancer Through Dual Targeting of Cancer Cells and Cancer Stem Cells: Evidence from In Vitro and In Vivo Models. Molecules2025, 30, 2377. https://doi.org/10.3390/molecules30112377

Jung H, Kim SY, Joo HG. Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma. Curr Issues Mol Biol. 2023 Nov 8; 45(11):8925-8938. Doi: 10.3390/cimb45110560. PMID: 37998737; PMCID: PMC10670425.

Park D. Fenbendazole Suppresses Growth and Induces Apoptosis of Actively Growing H4IIE Hepatocellular Carcinoma Cells via p21-Mediated Cell-Cycle Arrest. Biol Pharm Bull. 2022; 45(2):184-193. Doi: 10.1248/bpb.b21-00697. PMID: 35110505.

Chang CS, Ryu JY, Choi JK, Cho YJ, Choi JJ, Hwang JR, Choi JY, Noh JJ, Lee CM, Won JE, Han HD, Lee JW. Anti-cancer effect of Fenbendazole-incorporated PLGA nanoparticles in ovarian cancer. J Gynecol Oncol. 2023 Sep; 34(5):e58. Doi: 10.3802/jgo.2023.34.e58. Epub 2023 Apr 24. PMID: 37170725; PMCID: PMC10482585.

Jin IS, Jo MJ, Park CW, Chung YB, Kim JS, Shin DH. Physicochemical, Pharmacokinetic, and Toxicity Evaluation of Soluplus® Polymeric Micelles Encapsulating Fenbendazole. Pharmaceutics. 2020 Oct 21; 12(10):1000. Doi: 10.3390/pharmaceutics12101000. PMID: 33096915; PMCID: PMC7589096.

 

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Wearable Health Technology: Turning Pharmacovigilance from Reactive to Proactive and Predictive

by with No Comment Research

29 June 2025

Category:  Drug Safety | Health Technology |

Digital Health

Written by:

Utkarsha Patil, M.Pharm

Reviewed and Fact-Checked By:

Vikas Londhe, MPharm

ChatGPT Image Jun 29, 2025, 12_52_04 PM
Freepik.com

Pharmacovigilance is the phase of clinical trials that continues throughout the lifespan of the medicine. The main aim of pharmacovigilance is to collect clinical trial and post-marketing information related to the safety of medicine. To collect this information, pharmaceutical industries rely heavily on doctors and patients to voluntarily report safety information, which, unfortunately, often results in underreporting and delayed identification of adverse drug reactions (ADRs). Additionally, pharmaceutical industries take proactive steps in the form of different support programs through which they collect safety information, but that requires a lot of effort and increases the economic burden. On the other hand, the major drawback of clinical trials is that they do not provide real-world data, as trials are conducted in a very controlled manner.

In recent times, the popularity of wearable health devices is increasing; for example, smartwatches have almost replaced traditional wristwatches; people love to wear them. These smartwatches track the health data of the person without using any additional devices or any effort. Health data like heart rate, blood pressure, beats, oxygen level, step counts, and daily calories burned etc. have been recorded by Fitbit. These features of health devices are very beneficial in tracking any adverse events in patients, specifically cardiology events.

Hence, the landscape is evolving with the arrival of wearable health technology. Devices like these now facilitate continuous, real-time monitoring of physiological parameters, offering an additional, more proactive, and more comprehensive channel to gather safety information. As per one research published in PLOS Digital Health Journal on wearable devices in digital health, which focused on the main functions of these devices that are monitoring, screening, detection, and prediction, these functions closely resemble the basic principles of pharmacovigilance, i.e., monitoring, detecting, assessing, and understanding adverse events.

Benefits of Wearable Technologies

Wearables are becoming powerful health monitoring tools. As most of the devices work on batteries and are charged and worn throughout the day, they provide comprehensive health data continuously. This ability to continuously collect physiological data could start a new era in pharmacovigilance, where safety information can be observed in real-world settings with accuracy.

Real-Time, Round-the-Clock Monitoring: Wearables operate 24/7, capturing even slight changes in vital signs like irregular heartbeats or sudden blood pressure shifts that might go unnoticed. This allows for quicker identification of potential ADRs compared to traditional reporting methods.

Empowering Patients: These devices give users more control over their health. Patients can easily track their symptoms, receive alerts, and share data with healthcare providers, promoting better communication and medication adherence.

Real-World Evidence (RWE): As mentioned above, unlike controlled clinical trials, wearable data reflects what happens in real life. This helps researchers identify long-term or rare side effects across a broader and more diverse population.

Early Intervention: If a wearable detects warning signs, it can trigger a timely medical review. This allows doctors to adjust dosages, switch medications, or recommend other interventions before issues become serious.

Integration of Wearable Health Technology in Pharmacovigilance

Integration refers to the combination of wearable health devices and artificial intelligence (AI) systems to create a smart, responsive ecosystem that continuously monitors drug safety in real time.

How integration can work step by step

Data Collection from Wearables

Devices such as smartwatches, biosensors, fitness bands, or smart patches collect continuous physiological data, like heart rate changes, sleep cycles, ECG, physical activity, temperature, calorie burn, oxygen levels, glucose, etc.

Real-Time Analysis via AI/ML

These raw data channels are pushed into AI-powered platforms (cloud) that use machine learning algorithms to detect patterns or deviations. This analysis might include filtration of the data, identification of any significant patterns, and generation of actionable insights.

The AI continuously learns from population-level data and individual baselines to distinguish between normal variation and potential adverse drug reactions (ADRs).

Example: If a wearable detects repeated nighttime arrhythmias after a patient starts a new antihypertensive drug, the AI may flag this as a safety signal.

Connection with Digital Therapeutic Apps

Health Device Wearables are typically connected to mobile apps

These apps can:

  • Notify patients of detected abnormalities
  • Mobile apps may ask for symptom confirmation (e.g., “Are you experiencing dizziness or palpitations?”)
  • Prompt them to report side effects
  • Provide customized health advice or reminders

Automated Reporting & Pharmacovigilance Feedback Loops

  • If an ADR is suspected, the platform can generate an automated case report for healthcare providers or regulatory bodies.
  • These systems can be connected to electronic health records (EHRs) or pharmacovigilance databases like the FDA’s FAERS or EMA’s EudraVigilance, improving the speed and accuracy of safety signal detection.

Real-World Applications of Wearable & App Integration in Pharmacovigilance

1. Apple Heart Study—Stanford & Apple (Supported by FDA)

Apple, in collaboration with Stanford University, has conducted a study in approximately 500,000 participants to assess whether the Apple Watch can accurately detect atrial fibrillation (AFib), a potentially serious heart rhythm condition.

  • The Apple Watch continuously monitors users’ heart rhythms.
  • Data was sent to a dedicated app.
  • If an irregular rhythm was detected, users received a notification and were connected to a telemedicine consultation and an ECG patch for clinical confirmation.

This kind of continuous monitoring is now being considered for drug-induced arrhythmias, such as those caused by QT-prolonging medications (e.g., antipsychotics, antibiotics).

2. FDA’s Digital Health Software Precertification Program

Many health startups and companies have developed software that tracks various health-related data of individuals. As a result, this software generally functions similarly to medical devices. To address this, the FDA introduced a program based on the concept of Software as a Medical Device (SaMD). Under this framework, the FDA aims to fast-track the approval of trustworthy software and apps that collect, analyze, and act on health data, including those used for pharmacovigilance purposes.

Under this program, the AI-powered health apps are integrated with wearables (like Fitbit or Garmin) that can detect side effects from drugs (e.g., fatigue, arrhythmia, sleep disruption) to accelerate approval. These systems generate automated alerts to clinicians or researchers.

3. Propeller Health’s Bluetooth-connected Inhaler

Propeller Health (ResMed) focuses on digital respiratory health, particularly for conditions like asthma and COPD. Their system integrates Bluetooth-enabled inhaler sensors with mobile health apps to track medication usage patterns and environmental triggers. By analyzing this real-time data, the platform can detect signs of drug overuse, poor disease control, or adverse effects such as tremors and potential indicators of medication toxicity. This continuous monitoring supports pharmacovigilance efforts by identifying drug misuse, ineffectiveness, and side effects more accurately and contributes valuable safety data to regulatory and clinical databases.

4. Stanford University Studies Using Wearables for Vaccine Safety

During the COVID-19 pandemic, Stanford University partnered with Tel Aviv University to monitor post-vaccine side effects using wearable and mobile apps.

How It Worked:

  • Participants wore smartwatches and logged symptoms via an app.
  • Physiological data like resting heart rate, activity level, and sleep were analyzed for changes after vaccination.
  • Helped detect both expected side effects (like fever) and rare ones.

 This study showed how digital tools can enhance post-market surveillance for vaccines and could apply to drug safety monitoring as well.

5. Ongoing Clinical Trials Using Wearables for Drug Safety

Many current FDA-registered trials use wearables for pharmacovigilance-related outcomes:

  • Trials using continuous glucose monitors (CGMs) to monitor the safety of anti-diabetic drugs.
  • Smart patches monitor vitals in cancer patients receiving chemotherapy to detect early toxicity.

Special Considerations for Older Adults

Wearable technology has proven useful, especially for seniors. For example, it’s been used to detect medication-related changes in movement or behavior, such as excessive sedation or fall risk, offering insights into how drugs affect older populations in daily life.

Challenges of Wearable health technology

Despite its clear application in the healthcare system, including pharmacovigilance and clinical trials, this technology has some limitations that may hinder its true potential to be used in real-life settings; some of them are

  1. 1. Data Accuracy and Validation
  2. Privacy and Data Security Concerns
  3. Integration with Clinical and Regulatory Systems

Conclusion
Wearable health technology has laid the groundwork for a smarter and more responsive approach to drug safety. With the ability to collect real-time, significant data directly from users, these tools are turning pharmacovigilance from a reactive and proactive mode to a predictive mode, where users can predict the adverse event in real time. But to truly unlock their full potential, we must address challenges like privacy protection, device integration, and data reliability. If we work on these aspects, wearable-driven surveillance could reshape drug monitoring into something safer, more efficient, and tailored to individual needs.

Reference

Kalisch Ellett LM, Janetzki JL, Lim R, Laba TL, Pratt NL. Innovations in pharmacovigilance studies of medicines in older people. Br J Clin Pharmacol. 2025 Jan; 91(1):66-83. Doi: 10.1111/bcp.16049. Epub 2024 Mar 26. PMID: 38529693; PMCID: PMC11671332.

Jiang N, Mück JE, Yetisen AK. The Regulation of Wearable Medical Devices. Trends Biotechnol. 2020 Feb; 38(2):129-133. doi: 10.1016/j.tibtech.2019.06.004. Epub 2019 Jul 15. PMID: 31320119.

Muniappan S, Jeyaraman M, Yadav S, Applications of Blockchain-Based Technology for Healthcare Devices Post-market Surveillance. Cureus. 2024 Apr 8;16(4):e57881. doi: 10.7759/cureus.57881. PMID: 38725738; PMCID: PMC11079575.

Badnjević A, Pokvić LG, Deumić A, Bećirović LS. Post-market surveillance of medical devices: A review. Technol Health Care. 2022;30(6):1315-1329. Doi: 10.3233/THC-220284. PMID: 35964220.

Canali S, Schiaffonati V, Aliverti A (2022) Challenges and recommendations for wearable devices in digital health: Data quality, interoperability, health equity, fairness. PLOS Digit Health 1(10): e0000104. https://doi.org/10.1371/ journal.pdig.0000104

Wearable Technology in Healthcare: Types, Benefits, and Future of Medical Devices, topflight, https://topflightapps.com/ideas/wearable-technology-in-healthcare/

Kang HS, Exworthy M. Wearing the Future—Wearables to Empower Users to Take Greater Responsibility for Their Health and Care: Scoping Review. JMIR Mhealth Uhealth. 2022 Jul 13;10(7):e35684. doi: 10.2196/35684. PMID: 35830222; PMCID: PMC9330198.

Real-time Analytics and Interoperability in Wearable Health Technology: Revolutionizing Patient Care, ACL digital, https://www.acldigital.com/blogs/real-time-analytics-and-interoperability-wearable-health-technology-revolutionizing-patient

Perez MV, Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation, The New England Journal of Medicine, N Engl J Med 2019;381:1909-1917 DOI: 10.1056/NEJMoa1901183

Apple Heart Study, Stanford Medicine, https://med.stanford.edu/appleheartstudy.html

Stanford Medicine announces results of unprecedented Apple Heart Study, https://www.apple.com/newsroom/2019/03/stanford-medicine-announces-results-of-unprecedented-apple-heart-study/

The Software Precertification (Pre-Cert) Pilot Program: Tailored Total Product Lifecycle Approaches and Key Findings, Sep 2022, US FDA, https://www.fda.gov/media/161815/download

Asthma patients breathe easier with new Bluetooth inhalers, https://www.pbs.org/newshour/health/asthma-patients-breathe-easier-new-bluetooth-inhalers

Chan AHY, Pleasants et al, Digital Inhalers for Asthma or Chronic Obstructive Pulmonary Disease: A Scientific Perspective. Pulm Ther. 2021 Dec;7(2):345-376. DOI: 10.1007/s41030-021-00167-4. Epub 2021 Aug 11. PMID: 34379316; PMCID: PMC8589868.

Guan G, Mofaz M, Qian G, Patalon T, Shmueli E, Yamin D, Brandeau ML. Higher sensitivity monitoring of reactions to COVID-19 vaccination using smartwatches. NPJ Digit Med. 2022 Sep 9;5(1):140. doi: 10.1038/s41746-022-00683-w. PMID: 36085312; PMCID: PMC9461410.

104939

The Hidden Pain Pathway: Paracetamol (Acetaminophen) Metabolite AM404 Blocks Peripheral Sodium Channels – A New Mechanism Uncovered

by with No Comment Research

Medically Written and Reviewed By: Vikas Londhe, M.Pharm, Pharmacology

104939
Source: Freepik.com

For over a century, paracetamol (acetaminophen) has been one of the world’s most widely used analgesics and antipyretics. Despite its widespread use, its exact mechanism of action has remained unclear. It was long believed to work mainly by blocking certain enzymes called cyclooxygenases (COX), especially COX-2. These enzymes are responsible for producing prostaglandins, which are chemicals that promote pain, inflammation, and fever. By reducing prostaglandin production, paracetamol helps lower pain and fever without significantly reducing inflammation like other NSAIDs. However, it is believed that paracetamol is only effective in mild inflammations, like after tooth extraction, and it is not effective in severe inflammation that arises from rheumatoid arthritis and acute gout.

Another pathway involves the TRPV1 receptor, short for Transient Receptor Potential Vanilloid 1, which plays a role in sensing heat and pain. Some research suggests that an active metabolite of paracetamol, the fatty acid amide N-arachidonoylphenolamine (AM404), may activate TRPV1 in a way that leads to pain relief by desensitizing these pain-sensing receptors.

However, new research conducted at Hebrew University of Jerusalem and the findings are published in The Proceedings of the National Academy of Sciences (PNAS) has uncovered a previously unknown mechanism of paracetamol. The new research proposed that paracetamol acts directly at peripheral nerve endings. Its metabolite AM404 can block sodium channels in the nerves, which are essential for sending pain signals to the brain. This discovery adds a new dimension to our understanding of how paracetamol relieves pain: not just through the inhibition of certain enzymes and receptors, but also by directly inhibiting the body’s ability to send pain signals to the brain.

The Breakthrough Study

A team led by Professors Alexander Binshtok and Avi Priel from the Hebrew University of Jerusalem published these game-changing findings in the prestigious PNAS, titled “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels”

The key findings of the Research Includes

Local production of AM404: After oral intake of paracetamol, the body converts it to p-aminophenol in the liver, which is subsequently transformed into AM404 by fatty acid amide hydrolase (FAAH) in primary sensory neurons, essentially at the nerve endings where pain signals originate.

Inhibition of nociceptive sodium channels: AM404 directly blocks voltage-gated sodium channels Na_V1.7 and Na_V1.8, both crucial for generating action potentials in pain-sensing neurons. The blockade occurs via the local anesthetic binding site.

Peripheral analgesia: Through this localized mechanism, AM404 prevents pain signals at their source, producing potent relief in both regular and inflammatory pain models in rodents.

Researchers found that AM404, a metabolite formed from paracetamol in the body, accumulates in peripheral sensory neurons where it directly inhibits voltage-gated sodium channels Na_V1.7 and Na_V1.8. These channels are critical for the initiation and conduction of pain signals at the site of injury or inflammation. By blocking these sodium channels, AM404 effectively diminishes nociceptive signal transmission at its source, preventing pain before it even reaches the spinal cord. This peripheral action represents a fundamental shift in our understanding of how paracetamol works. It positioned paracetamol not only as a central analgesic but also as a locally acting modulator of neuronal excitability.

Results

AM404 significantly reduced sodium current amplitude in isolated dorsal root ganglion (DRG) neurons in a dose-dependent manner. The greatest effect was observed on tetrodotoxin-resistant (TTX-R) sodium currents, which are characteristic of Nav1.8, a key player in chronic and inflammatory pain. AM404 had minimal effect on potassium and calcium currents, indicating a selective action on sodium channels.

In pharmacological profiling, AM404 showed the strongest inhibition of Nav1.7 and Nav1.8, both of which are highly expressed in nociceptive (pain-sensing) neurons. Other Nav subtypes, such as Nav1.5 (cardiac) and Nav1.6 (CNS), were minimally affected, suggesting a favorable safety profile by avoiding cardiac or CNS toxicity.

In formalin-induced inflammatory pain models, peripheral injection of AM404 significantly reduced both early (neurogenic) and late (inflammatory) phases of pain behaviors (licking, flinching). In the hot plate and tail flick thermal assays, AM404 increased latency to pain response, indicating effective thermal analgesia. Systemic or central (intrathecal) administration of AM404 had less prominent effects, highlighting that peripheral action is essential for its analgesic activity.

Computational docking predicted that AM404 binds to a hydrophobic fenestration site within the channel’s domain IV S6 segment, a region known to influence channel gating and drug binding.

Implications

This research challenges the traditional view of paracetamol as a centrally acting analgesic. It highlights that peripheral mechanisms, particularly in the context of inflammatory pain, are also crucial to its analgesic action. A key finding is the active pharmacological role of AM404, a metabolite of paracetamol, which is not just a metabolic byproduct but a potent modulator contributing to its pain-relieving effects. This adds to the recognition of the importance of drug metabolites in determining therapeutic efficacy. Moreover, the study strengthens the therapeutic relevance of targeting sodium channel subtype Na_V 1.7, positioning AM404 as a promising lead compound or molecular scaffold for the development of new, non-opioid analgesics.

Broader Impact: Beyond Paracetamol

This study opens exciting new avenues in the field of pain research. It triggers a re-evaluation of some metabolites that have been silent since their discovery and are also traditionally overlooked, but may possess key pharmacological actions, suggesting that other commonly used drugs could harbor unexplored therapeutic potential through their metabolites.

Additionally, the findings strengthen the scientific rationale for targeting peripheral sodium channels, particularly in managing chronic and inflammatory pain conditions. AM404, a paracetamol metabolite, exerts analgesic effects without causing sedation or respiratory depression, positioning it as a promising foundation for developing safer, non-addictive alternatives to opioids.

Conclusion

The discovery that AM404 blocks peripheral NaV channels redefines how we understand one of the worlds’s most commonly used analgesics. By uncovering this hidden peripheral pain pathway, researchers at the Hebrew University of Jerusalem have significantly advanced the field of analgesic pharmacology. This work not only deepens our molecular understanding of paracetamol but also opens up new possibilities for developing better pain medicines and emphasizing the vital role of peripheral targets in pain relief.

References

Y Maatuf, Y. Kushnir, A.Nemirovski, et al, The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels, Proc. Natl. Acad. Sci. U.S.A. 122 (23) e2413811122, https://doi.org/10.1073/pnas.2413811122

Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008 Oct; 18(10):915-21. Doi: 10.1111/j.1460-9592.2008.02764.x. PMID: 18811827

Israeli study finds acetaminophen drug works by first blocking pain in nerves, The Times of Israel, https://www.timesofisrael.com/israeli-study-finds-acetaminophen-drug-works-by-first-blocking-pain-in-nerves/

New discovery: Tylenol stops pain at the nerves, before it hits the brain, ScienceDaily, https://www.sciencedaily.com/releases/2025/06/250610074247.htm#:~:text=Summary%3A,channels%20in%20pain%2Dsensing%20nerves.

Mallet C, Desmeules J, Pegahi R, Eschalier A. An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact. J Pain Res. 2023 Mar 29;16:1081-1094. Doi: 10.2147/JPR.S393809. PMID: 37016715; PMCID: PMC10066900.

Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, Mehta V, First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid. J Pain Res. 2017; 10:2703-2709 https://doi.org/10.2147/JPR.S143500

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“Treating Spinal Muscular Atrophy (SMA) in the Womb: Early Evidence for Prenatal Risdiplam Therapy”

by with No Comment Research

Written and Reviewed By:  Vikas Londhe (M.Pharm, Pharmacology)

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Source: Freepik.com

Spinal muscular atrophy (SMA) is a rare but serious genetic neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord. This leads to progressive muscle weakness, respiratory failure, and early mortality. The severity of the disease varies depending on the number of SMN2 gene copies an individual has, with type 0 SMA being the most severe and typically fatal in the prenatal or neonatal period.

A pioneering new study, recently published in The New England Journal of Medicine, presents the administration of risdiplam, a gene-modifying therapy, during pregnancy to a fetus who is at risk of being diagnosed with SMA. Risdiplam, an orally available small-molecule drug, works by modifying the splicing of the SMN2 gene to increase production of functional SMN protein, which is essential for motor neuron survival.

This is the first-of-its-kind prenatal intervention that has shown potential to revolutionize the treatment of SMA, particularly for the most lethal forms of the disease. By initiating therapy before birth, researchers hope to prevent the irreversible loss of motor neurons in utero, offering the potential for normal neuromuscular development and vastly improved outcomes. The implications of this study are thoughtful which indicates a proactive and early management of this devastating condition.

Background: Understanding SMA and Risdiplam

Spinal muscular atrophy (SMA) is primarily caused by a genetic mutation in the SMN1 gene, which leads to a deficiency of the survival motor neuron (SMN) protein. This protein is essential for the health and function of motor neurons, nerve cells that control voluntary muscle activity such as walking, breathing, and swallowing.

In healthy individuals, the SMN1 gene produces adequate amounts of full-length SMN protein. However, in individuals with SMA, the SMN1 gene is either missing or nonfunctional, resulting in a reduction in SMN protein levels.

The body does have a natural backup in the form of the SMN2 gene, a nearly identical copy of SMN1. But due to a single nucleotide difference, the SMN2 gene undergoes inefficient splicing, leading to the exclusion of exon 7 in most transcripts. As a result, only a small fraction of functional SMN protein is produced from SMN2 typically not enough to fully counterbalance for the loss of SMN1. This imbalance in SMN protein production leads to motor neuron degeneration and the progressive muscle weakness characteristic of SMA. The number of SMN2 copies a person has can influence disease severity: more copies generally correlate with milder forms of SMA.

Risdiplam is a small molecule SMN2 splicing modifier approved for treating SMA in patients two months and older. It works by promoting exon 7 inclusions during SMN2 pre-mRNA splicing, thus increasing the production of functional SMN protein.

Study Highlights: N-of-1: A case study of prenatal risdiplam 

This study represents the first documented case of prenatal risdiplam therapy in a foetus that was at risk of developing type 1 spinal muscular atrophy (SMA). This inference was drawn because the fetus’s older deceased sibling had a genetically confirmed diagnosis of type 1 SMA. The fetus was tested by amniocentesis and confirmed to have Type 1 SMA, which is characterized by a complete absence of the SMN1 gene and two copies of the SMN2 gene. This genetic profile leads to minimal production of functional SMN protein, resulting in early motor neuron degeneration, evident as reduced fetal movement, joint contractures, and respiratory failure shortly after birth. Without intervention, type 1 SMA usually leads to death in the neonatal period, making early diagnosis and potential treatment critical.

Key Aspects of the Study

This landmark case of prenatal risdiplam therapy began with early genetic detection and a carefully monitored treatment strategy:

Prenatal Diagnosis: The foetus was diagnosed with spinal muscular atrophy (SMA) type 1 through amniocentesis and also from the previous family history of type 1 SMA diagnosed in older sibling who is unfortunately died at 16 months of age. To add this, the parents were both known carriers of SMA genetic variants. Genetic testing revealed a complete absence of the SMN1 gene and the presence of two copies of SMN2. This pattern is diagnostic of type 1 SMA, the severe form, which often results in death shortly after birth.

Approval and availability of risdiplam: The local institutional board, followed by the USFDA, has approved the single-patient investigational therapy. F. Hoffmann-La Roche has provided advice on the safety of prenatal exposure to risdiplam, along with a supply of risdiplam at no cost due to a confidentiality agreement with sponsor St. Jude Children’s Research Hospital. Parents have provided informed consent.

Initiation of Therapy: With a confirmed diagnosis and serious prognosis, the risdiplam was administered to the mother orally. The dosing was adjusted to 5 mg once per day. The risdiplam was administered from 32 weeks 5 days of gestation up to delivery at 38 weeks 6 days of gestation. However, the fetus continued to be administered risdiplam daily post-delivery from 8 days of birth to the present time (30 months of age in February 2025).

Monitoring: The mother had weekly checkups to monitor her pregnancy health and for any side effects from the medication. The fetus was also regularly checked using ultrasound to monitor growth, movement, and overall development.

Outcomes and Findings

The infant appeared healthy at birth but was later found to have a heart murmur caused by a ventricular septal defect, which resolved on its own. The child also has slightly reduced vision and experienced brief episodes transient fixation nystagmus, linked to underdevelopment of the optic nerves in both eyes. Additionally, mild weakness on the right side of the body (right hemiparesis) was observed, associated with underdevelopment of the left midbrain. The infant has shown global developmental delays but has not experienced any waning of skills. The child has not shown any signs of spinal muscular atrophy (SMA) such as low muscle tone, muscle weakness, absence of reflexes, or muscle twitching. Motor function, muscle imaging (ultrasound), and nerve tests (electrophysiology) have been conducted every six months and consistently show normal development of nerves and muscles for the child’s age.

The blood sample results revealed increased levels of SMN protein and lower neurofilament levels, which indicates the drug successfully reached its intended target and had a positive effect on motor neuron development. The above-mentioned congenital abnormalities seen in the infant were believed to have occurred early in fetal development before risdiplam treatment began, and no specific cause was identified. Animal studies also support this claim, where risdiplam was given during prenatal and postnatal stages, and no abnormalities have occurred in them.

While this is just a single case and the results cannot be widely applied, the findings suggest that prenatal risdiplam therapy could be a promising option for treating SMA when diagnosed before birth.

Significance and Implications

This study represents the first documented case of prenatal risdiplam therapy in humans, offering proof-of-concept that in utero intervention can alter the course of spinal muscular atrophy (SMA) even in its severe form, type 1. By initiating treatment during fetal development, before irreversible motor neuron loss occurs, this case displays the potential to preserve neuromuscular function, improve survival outcomes, and redefine the clinical management of SMA.

While results are based on a single case, the findings open the door to a new era of prenatal therapies for genetic neurodegenerative disorders. Future research will determine whether prenatal risdiplam should become part of the standard of care for high-risk SMA pregnancies. For now, it offers a glimpse of hope for families facing this devastating diagnosis.

Reference

Finkel RS, Hughes SH, Parker J, Civitello M, Lavado A, Mefford HC, Mueller L, Kletzl H; Prenatal SMA Risdiplam Study Group. Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy. N Engl J Med. 2025 Mar 13;392(11):1138-1140. doi: 10.1056/NEJMc2300802. Epub 2025 Feb 19. PMID: 39970420.

Promising results from first prenatal therapy for spinal muscular atrophy, 19 Feb 2025, St. Jude’s Childrens Hospital, https://www.stjude.org/media-resources/news-releases/2025-medicine-science-news/promising-results-from-first-prenatal-therapy-for-spinal-muscular-atrophy.html

Treating spinal muscular atrophy in the womb, nature medicine, https://www.nature.com/articles/d41591-025-00017-9

Kakazu J, Walker NL, Babin KC, et al, Risdiplam for the Use of Spinal Muscular Atrophy. Orthop Rev (Pavia). 2021 Jul 12;13(2):25579. Doi: 10.52965/001c.25579. PMID: 34745484; PMCID: PMC8567805.

Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015 Nov;33(4):831-46. Doi: 10.1016/j.ncl.2015.07.004. PMID: 26515624; PMCID: PMC4628728.

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“Saarvienin A: A Novel Antibiotic from Rare Earth Mine in China Targets Vancomycin-Resistant Gram-Positive Bacteria”

by with No Comment Research

Written by: Utkarsha Patil (M.Pharm, Pharmacology)

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Source: Freepik.com

The growing threat of antimicrobial resistance (AMR) strengthens the urgent need to search for novel therapeutic agents. Amid this growing worry, a promising new antibiotic known as Saarvienin A has surfaced. Saarvienin A was isolated from a rare environmental actinomycete Amycolatopsis species.

Saarvienin A was identified by an international research team led by scientists from the University of Vienna and the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS). The antibiotic was isolated from a strain of Amycolatopsis sp. YIM10, a soil-dwelling actinobacterium collected from a rare earth mine in China. Amycolatopsis is known for producing clinically important antibiotics like vancomycin.

Saarvienin A has attracted significant scientific interest due to its potent activity against multidrug-resistant infections. It is thought that Saarvienin A operates by a new mechanism due to its unique structure, which does not resemble any other glycopeptides, including vancomycin. This uniqueness will be the factor that works against drug-resistant bacteria, particularly against Staphylococcus aureus, especially methicillin-resistant strains (MRSA), making it a convincing candidate in the fight against resistant pathogens.

A Unique Habitat

The rare earth mining environment of Southern China is harsh, mineral-rich, and has biologically unique conditions that challenge microbial life and promote the production of uncommon secondary metabolites. During a targeted bioprospecting journey, researchers collected soil samples from this ecosystem. After doing an extensive analysis of this sample, scientists isolated Amycolatopsis sp. YIM10, a previously uncultured strain of actinobacteria.

This strain belonged to the prolific genus Amycolatopsis, known for producing the clinically important rifamycin antibiotics. Still, YIM10 was distinctive because scientists discovered something unusual harbored by this species: biosynthetic gene cluster (BGCs) that encodes previously unexplored compounds.

Saarvienin A

Amycolatopsis sp. YIM10 having rich reservoir of biosynthetic gene clusters (BGCs). Scientist discovered only few secondary metabolites identified in fermentation broth or via genome mining and all of these metabolites had no or very weak antimicrobial activity.  However, some culture extracts showed a significant antimicrobial effect. Further fractionation of these extracts identified a new glycopeptide, which they named it Saarvienin A, to recognize and show appreciation for Saarland, Germany, where part of the research was conducted.

Detailed NMR and mass spectrometry analyses revealed that the compound features a pentasugar/aminosugar chain attached to a halogenated peptide core, with three of its four amino acids forming a macrocyclic structure via a urea-type carbonyl linkage. A SciFinder structural similarity search identified vancomycin derivatives as the closest known compounds, even though they are structurally distinct. This suggests that the compound referred to as saarvienin A represents a novel class of glycopeptides. It can distinguish by its ability to overcome vancomycin resistance and exhibit selective antibacterial activity against Gram-positive pathogens.

The spectrum of activity

The in vitro antibacterial activity of Saarvienin A was evaluated against a range of Gram-positive and Gram-negative pathogens. It exhibited potent activity against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE), methicillin-resistant and vancomycin-intermediate Staphylococcus aureus (MRSA/VISA), and Daptomycin-resistant S. aureus (DRSA).

Saarvienin A showed minimum inhibitory concentrations (MICs) of 1 µg/mL against Enterococcus faecalis (vanB-positive) and Enterococcus faecium (vanA-positive), significantly surpassing the efficacy of vancomycin. It also demonstrated low MICs against MRSA/VISA and DRSA strains. Saarvienin A showed moderate activity against Mycobacterium smegmatis but was less effective against Mycobacterium tuberculosis.

In contrast, it lacked activity against Gram-negative bacteria, including Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa. This lack of efficacy is likely due to its inability to penetrate the outer membrane barrier of Gram-negative organisms.

Mechanism of Action

In the initial discovery and characterization studies, researchers identified its strong antibacterial activity especially against Gram-positive, drug-resistant pathogens but did not yet determine the precise molecular target or how it exerts its antibacterial effect. However, some early evidence suggests that Saarvienin A may represent a new class of glycopeptides-like compounds, structurally distinct from existing antibiotics such as vancomycin. Because it shows activity against vancomycin-resistant and daptomycin-resistant strains, it likely acts through a novel or modified mechanism, different from known glycopeptides antibiotics.

Safety

The cytotoxicity of Saarvienin A was evaluated using the HepG2 human liver carcinoma cell line, revealing an IC₅₀ of 13 µg/mL, This suggests a potential therapeutic window. The observed cytotoxic effects highlight the need for further structural optimization to improve selectivity and minimize toxicity, despite the compound’s promising antibacterial activity.

Implications and Conclusion

The discovery of Saarvienin A represents a significant milestone in the ongoing battle against antimicrobial resistance, especially among Gram-positive pathogens. Isolated from Amycolatopsis sp. YIM10, a strain collected from a rare earth mine in China. These novel glycopeptides show potent antibacterial activity against vancomycin-resistant and daptomycin-resistant strains, including VRE and MRSA/VISA.

Saarvienin A’s novel structure and potential mechanism of action, suggesting it could form the basis of a new class of glycopeptides. Despite its promising activity, particularly against drug-resistant Gram-positive bacteria, its limited effect on Gram-negative pathogens and observed cytotoxicity underscore the need for further structural optimization and preclinical evaluation.

The findings highlight the potential of extreme and underexplored ecosystems, such as rare earth mining environments, in yielding unique microbial metabolites with therapeutic potential. As resistance to existing antibiotics continues to rise, Saarvienin A serves as a gripping lead compound for the development of next-generation antibiotics capable of overcoming established resistance mechanisms.

References

Amninder Kaur, Jaime Felipe Guerrero-Garzón, Sari Rasheed, et al, Saarvienin A—A Novel Glycopeptide with Potent Activity against Drug-Resistant Bacteria, Angew. Chem. Int. Ed. 2025, e202425588, doi.org/10.1002/anie.202425588

Liu L, Liu Y, Liu S, Nikandrova, et al, (2023) Bioprospecting for the soil-derived actinobacteria and bioactive secondary metabolites on the Western Qinghai-Tibet Plateau. Front. Microbiol. 14:1247001. doi: 10.3389/fmicb.2023.1247001

Scientists discover first “Saar-drug“, Saarvienin A shows promising properties for combating resistant hospital germs, Helmholtz Centre for Infection Research, https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/scientists-discover-first-saar-drug/

Li T, Yu X, Li M, Rong L, Xiao X, Zou X. Ecological insight into antibiotic resistome of ion-adsorption rare earth mining soils from south China by metagenomic analysis. Sci Total Environ. 2023 May 10;872:162265. doi: 10.1016/j.scitotenv.2023.162265. Epub 2023 Feb 17. PMID: 36801324.

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

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“The Curious Case of KJ: How the World’s First CRISPR-Cas9 Gene Editing Therapy Saved a Child from Fatal CPS1 Deficiency”

by with No Comment Research

Written by: Shital Gaikwad M.Pharm (Pharmacology)

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Source: Freepik.com

In a landmark medical breakthrough, a young child identified only as KJ became the first known patient to be successfully treated for a fatal genetic disorder using CRISPR gene editing inside the body. Researchers used a customized, CRISPR-based therapy to treat carbamoyl phosphate synthetase 1 (CPS1) deficiency, a rare and life-threatening genetic condition. This represents the first clinical application of a personalized CRISPR treatment tailored to an individual patient. KJ’s remarkable recovery is not only his triumph but also a significant milestone for genomic medicine, which offers a new hope for treating ultra-rare genetic diseases and paving the way for future individualized therapies.

What Is CPS1 Deficiency?

Carbamoyl Phosphate Synthetase 1 (CPS1) deficiency is an ultra-rare genetic disorder characterized by the liver’s inability to fully break down byproducts of protein metabolism, leading to a toxic buildup of ammonia in the body. The enzyme carbamoyl phosphate synthetase 1, encoded by the CPS1 gene, is essential for the urea cycle; a process that converts ammonia, a byproduct of protein breakdown, into urea to prevent harmful accumulation. Urea is then safely excreted from the body. Mutations in the CPS1 gene results in CPS1 deficiency, a hereditary urea cycle disorder that impairs the body’s ability to eliminate excess nitrogen. In the absence of this enzyme, ammonia accumulates in the blood, a condition known as hyperammonemia, which can lead to serious brain damage, coma, or even death, particularly in infants.

This condition typically presents within the first few days after birth, with symptoms like vomiting, lethargy, seizures, and difficulty breathing. The prognosis is poor, even with aggressive treatment such as dialysis or protein-restricted diets. Medication includes ammonia-scavenging agents and citrulline supplementation. These short-term management strategies are limited in effectiveness, as even slight sickness or dehydration can trigger sudden and potentially fatal organ failure.

Enter CRISPR: A Genetic Scalpel

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a cutting-edge gene-editing technology that allows scientists to cut, remove, or replace faulty DNA sequences formed during mutation with high precision. Originally discovered as a natural defense system in bacteria, CRISPR functions like an immune system. Bacteria use it to recognize and destroy invading viral DNA. Scientists discovered that this bacterial defense mechanism could be adapted to precisely edit genes in other organisms, including humans.

While CRISPR has been widely used in research laboratories and clinical trials, editing DNA directly inside a living human body represents a giant leap in medicine and has never before been attempted to treat CPS1 deficiency.

How CRISPR Works: Step-by-Step

Guide RNA Design: Scientists create a synthetic RNA molecule called a guide RNA (gRNA) that matches the specific faulty DNA sequence targeted for editing.

Cas9 Binding: The guide RNA directs the Cas9 enzyme to the exact location of the faulty DNA within the genome.

DNA Cutting: Cas9 acts like molecular scissors, cutting the DNA precisely at the target site.

Repair or Rewrite: Scientists introduce a healthy copy of the gene, a template or blueprint which the cell can use to repair the cut DNA through a process called homology-directed repair (HDR). This allows the faulty gene to be corrected accurately.

KJ’s Journey: From Diagnosis to a CRISPR-Enabled Recovery

A Shocking Diagnosis

KJ was born as a healthy baby. But within 48 hours of birth, his condition deteriorated, he began vomiting, became unusually sleepy, and had trouble breathing. The blood test results were shocking. KJ’s blood showed extremely high levels of ammonia, 1000 μmol/liter (reference range, 9 to 33 μmol/liter). The plasma amino acid report revealed a vitally elevated level of glutamine, undetectable citrulline, and a normal level of urinary orotic acid. These findings were indicative of a proximal urea-cycle defect, a clear sign that something was wrong with his metabolism. Further genetic testing confirmed that the Q335X variant is absent in the Genome Aggregation Database. The absence of the Q335X variant suggests that this mutation is extremely rare or not typically found in the general population. However, it has been previously reported in one case of neonatal-onset CPS1 deficiency. Based on this genetic finding, the rare and life-threatening diagnosis of CPS1 deficiency was made. This disorder is so rare that it affects fewer than 1 in 1 million babies worldwide.

This condition meant that KJ’s liver lacked a critical enzyme needed to remove ammonia from his blood. Every time he ate protein, even small amounts found in baby formula, his body built up toxic levels of ammonia that could damage his brain or cause death within hours.

Early Treatments: A Desperate Race against Time

KJ’s care team at Children’s Hospital of Philadelphia (CHOP) immediately began intensive treatment to manage his condition. The treatment plan included:

Dialysis, to rapidly remove excess ammonia from his bloodstream

Nitrogen-scavenger medication (glycerol phenylbutyrate), to help eliminate nitrogen through alternative pathways

Citrulline supplementation, administered at 200 mg per kilogram of body weight per day, a dose that remained consistent throughout his clinical course

Strict protein restriction, to minimize ammonia production

Frequent hospitalizations, triggered even by minor infections or dietary errors

Despite these aggressive interventions, the severity of KJ’s condition continued to deteriorate. By the age of five months, he was scheduled to undergo a liver transplant, a last-resort option for managing his life-threatening disorder.

A Radical Option: CRISPR Gene Editing

As the time running out, doctors decided to use CRISPR technology to correct mutated gene. As a result, the therapy was created by a team at the Children’s Hospital of Philadelphia (CHOP), specifically within the Raymond G. Perelman Centre for Cellular and Molecular Therapeutics, in collaboration with genetic medicine experts, including Dr. Kiran Musunuru and Dr. Rebecca C. Ahrens-Nicklas, as well as Acuitas Therapeutics, which provided the lipid nanoparticle (LNP) delivery system. This was not a commercial pharmaceutical effort but rather a personalized, hospital-based investigational therapy, an example of an N-of-1 gene editing treatment tailored for a single patient.

To develop the therapy, researchers needed to correct the patient’s Q335X nonsense mutation in the CPS1 gene. Since primary human hepatocytes with the mutation were not available, they used a HuH-7 liver cancer cell line as a surrogate. Into these cells, they inserted a synthetic DNA cassette containing the patient’s specific mutation and other relevant sequences using a lentiviral vector. They then tested a range of adenine base editors (ABEs) and guide RNAs (gRNAs) to find the most effective and precise combination for correcting the mutation. The final chosen tools were NGC-ABE8e-V106W, a highly specific base editor, and a gRNA that positioned the target adenine in the ideal editing location. Their tests confirmed that the edits were successful and that any bystander edits were synonymous, meaning they did not alter the resulting protein.

The components of this custom therapy were uniquely named to reflect their personalized design. The selected guide RNA (gRNA) was called “kayjayguran“ and the messenger RNA (mRNA) encoding the base editor was named “abengcemeran.” The complete therapy, comprising both components and delivered via lipid nanoparticles, was referred to as “k-abe.” These names helped distinguish the patient-specific formulation from general-purpose gene editing tools.

The administration of the therapy was carried out intravenously. The gRNA and base editor mRNA were encapsulated in lipid nanoparticles using Acuitas Therapeutics’ proprietary LNP technology, including ionizable lipids and stabilizers designed for efficient liver targeting. The patient received three intravenous infusions of the therapeutic particles. This delivery method ensured that the gene-editing components reached the liver, the organ responsible for expressing the CPS1 gene. Post-treatment monitoring showed evidence of successful gene editing and improvement in metabolic function, marking this as a milestone in personalized medicine.

freepik__an-abstract-artistic-representation-of-crisprcas9-__28061

Source: The Children’s Hospital of Philadelphia (YouTube)

A Breakthrough in Medicine: Personalized Gene Editing to Save KJ

Source: Freepik.com

Successful Outcome and Impact

KJ experienced significant clinical improvement following treatment. Blood ammonia levels returned to normal, significantly lowering the risk of neurological injury. Liver function tests also began to normalize, suggesting that metabolic function was being restored. Remarkably, KJ avoided additional metabolic crises, which are often fatal in untreated CPS1 deficiency.

In terms of nutritional recovery, KJ was able to tolerate increased dietary protein, a key sign of improved urea cycle function. Additionally, there was a reduced dependence on ammonia-scavenging medications, reflecting the therapy’s effectiveness in correcting the underlying metabolic defect.

Broader Implications

This achievement not only saved the life of a KJ but also represents a potential paradigm shift in how rare genetic disorders are treated. The project received support through various federal initiatives, including the NIH’s Somatic Cell Genome Editing (SCGE) program, and benefited from in-kind contributions by biotech collaborators such as Acuitas Therapeutics, Integrated DNA Technologies, Aldevron, and the Danaher Corporation.

“This is a platform technology with the potential to lead in a new era of precision medicine for hundreds of rare diseases,” said Dr. Joni Rutter, Director of the National Centre for Advancing Translational Sciences (NCATS).

Dr. Kiran Musunuru added, “Our ambition is to apply this strategy across a wide range of rare diseases so more patients can access life-saving therapies. This represents the future of medicine.”

Conclusion

This case powerfully demonstrates the practicability  of individualized gene editing, often referred to as N of 1 therapy, “highly customized treatments designed for a single patient. It highlights the adaptability and precision of CRISPR-Cas9 technology in addressing even the rarest and life-threatening genetic disorders.

Beyond its scientific success, the therapy offers renewed hope to patients and families affected by ultra-rare conditions that were once considered untreatable due to their uniqueness. Notably, in this case, the FDA played a key role by allowing the therapy to proceed based on preclinical studies, enabling a rapid response to a life-threatening condition. This pioneering effort may influence future regulatory frameworks, promoting more compassionate and flexible pathways that support the accelerated development and approval of personalized genetic therapies.

The scientists presented their groundbreaking work at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting on May 15 and published the study in The New England Journal of Medicine.

References

Musunuru K, et al. “Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease.” New England Journal of Medicine. Published online May 15, 2025. DOI: 10.1056/NEJMoa25

Regalado, A. (2024, May 17). CRISPR gene editing used to treat baby with rare genetic disease. MIT Technology Review. https://www.technologyreview.com/2024/05/17/crispr-therapy-cps1-deficiency

Infant with rare, incurable disease is first to successfully receive personalized gene therapy treatment, News Releases, National Institute of Health, May 15, 2025, https://www.nih.gov/news-events/news-releases/infant-rare-incurable-disease-first-successfully-receive-personalized-gene-therapy-treatment

World’s First Patient Treated with Personalized CRISPR Gene Editing Therapy at Children’s Hospital of Philadelphia, May 15, 2025, Children’s Hospital of Philadelphia, https://www.chop.edu/news/worlds-first-patient-treated-personalized-crispr-gene-editing-therapy-childrens-hospital

Noori M, Jarrah O, Al Shamsi A. Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review. Mol Genet Metab Rep. 2024 Oct 18;41:101156. Doi: 10.1016/j.ymgmr.2024.101156. PMID: 39469307; PMCID: PMC11513499.

Carbamoyl phosphate synthetase I deficiency, Health Resource and Service Administration, https://newbornscreening.hrsa.gov/conditions/carbamoyl-phosphate-synthetase-i-deficiency

Li Q, Gao Y, Wang H. CRISPR-Based Tools for Fighting Rare Diseases. Life (Basel). 2022 Nov 24; 12(12):1968. Doi: 10.3390/life12121968. PMID: 36556333; PMCID: PMC9787644.

Amneet Kaur Badwal, Sushma Singh, A comprehensive review on the current status of CRISPR based clinical trials for rare diseases, International Journal of Biological Macromolecules, Volume 277, Part 2, 2024, 134097, https://doi.org/10.1016/j.ijbiomac.2024.134097.

Li, T., Yang, Y., Qi, H. et al. CRISPR/Cas9 therapeutics: progress and prospects. Sig Transduct Target Ther 8, 36 (2023). https://doi.org/10.1038/s41392-023-01309-7

American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, 15 May 2025, Conference presentation and press release.

The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com

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“Microplastics in Human Tissues: Insights from Nature Medicine and NEJM Studies”

by with No Comment Research

Written By Lavanya Chavhan B.Pharm

Reviewed and Fact Checked By Vikas Londhe M.Pharm (Pharmacology)

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Source: Freepik.com

Microplastics and nanoplastics (MNPs) tiny particles resulting from the degradation of plastic materials have rapidly become a focus of global health research. Two landmark studies published in Nature Medicine and The New England Journal of Medicine (NEJM) offer critical insights into the bioaccumulation and health consequences of these particles in human tissues. Together, they present an urgent call to re-evaluate the long-term implications of environmental plastic pollution.

Brain Accumulation and Neurological Concerns: Findings from Nature Medicine

A study published in Nature Medicine (April 2025) examined the presence of MNPs in human tissues, with a focus on liver, kidney, and brain samples from autopsies conducted in 2016 and 2024. The researchers used advanced analytical techniques including pyrolysis gas chromatography mass spectrometry (Py-GC/MS), electron microscopy, and Fourier-transform infrared spectroscopy to identify and quantify plastic particles.

Key Findings

Ubiquitous Presence: MNPs were detected in all three organs, but brain tissues exhibited the highest concentrations, 7 to 30 times greater than liver or kidney.

Polyethylene (PE) Dominance: PE accounted for approximately 75% of the plastic content in brains.

Temporal Trends: There was a significant increase in plastic concentrations between 2016 and 2024, reflecting rising environmental exposure.

Dementia Link: Brains of individuals with documented dementia had markedly higher levels of MNPs up to 26,076 µg/g suggesting a possible connection with neurodegenerative processes

Tissue Localization: Nanoplastics were found in brain parenchyma, immune cells, and cerebrovascular walls, raising questions about blood-brain barrier integrity and inflammatory responses.

Conclusion: Although the study does not establish causality, it strongly suggests that chronic exposure to MNPs may be associated with neurological vulnerability. The findings warrant deeper exploration into how plastic particles reach and affect brain tissue, particularly in individuals with compromised neurological health.

Cardiovascular Risks and Atheroma Infiltration: NEJM Study

The NEJM study (March 2024) provided the first direct clinical evidence linking MNPs to cardiovascular risk. It was a multicenter, prospective study involving 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease.

Key Findings:

MNP Detection: In 58.4% of patients, polyethylene was found within atherosclerotic plaques. Polyvinyl chloride was also detected in 12.1%.

Nanoplastics Inside Plaques: Electron microscopy revealed jagged-edged particles (<1 µm) embedded in foam cells and extracellular plaque matrix.

Increased Cardiovascular Events: Over a 34-month follow-up, patients with MNP-positive plaques were at 4.5 times greater risk of myocardial infarction, stroke, or death compared to those without detectable plastics.

Inflammation Correlation: Elevated levels of interleukin-1β, IL-6, TNF-α, and CD68 were observed in MNP-positive plaques, suggesting heightened inflammatory responses.

Conclusion: The presence of MNPs in vascular tissues appears to be more than incidental. It correlates with both histological inflammation and clinically significant cardiovascular outcomes. This raises red flags about MNPs as emerging risk factors in heart and vascular diseases.

Implications for Human Health and Future Research

The convergence of findings from brain and vascular tissues paints a concerning picture:

Bioaccumulation is Organ-Specific: MNPs preferentially accumulate in certain tissues, potentially due to local physiological characteristics like vascular density or barrier permeability.

Health Impact is Multisystemic: While one study implicates MNPs in neurodegeneration, the other links them to cardiovascular events two of the most pressing areas in public health.

Mechanistic Gaps Remain: Both studies acknowledge the limitations in establishing causality. The exact pathways of MNP absorption, translocation, and clearance in humans remain poorly understood.

Another small study presented in American Heart Association conference

At the American Heart Association’s Vascular Discovery Scientific Sessions held in Baltimore on April 22, 2025, researchers presented compelling evidence linking microplastics to vascular disease. The study, led by Dr. Ross Clark from the University of New Mexico, analyzed carotid artery plaques from individuals who had experienced strokes, mini-strokes, or transient vision loss. Findings revealed that these plaques contained microplastics at concentrations 51 times higher than those in healthy arteries. Notably, polyethylene and polyvinyl chloride were the predominant plastics detected. While the study did not establish a direct causal relationship, it highlighted a strong association between microplastic accumulation and symptomatic arterial disease, underscoring the need for further research into the potential health impacts of environmental plastic exposure.

Conclusion

As plastic production continues to grow rapidly across the globe, recent studies serve as a strong warning that we must take urgent action. This includes putting better regulations in place, increasing scientific research, and raising public health awareness. Tiny plastic particles known as microplastics and nanoplastics are now found in the air we breathe, the food we eat, and even in our bodies. These particles may carry harmful chemicals and can travel through the blood stream to vital organs. Over time, long term exposure to them could increase the risk of serious health problems, including disease of the brain, heart, lungs and more.

To truly understand how these plastics affect our health, we need experts from many different fields to work together. Toxicologists can study how the plastics interact with our cells, neurologists can explore their impact on the brain and nervous system, cardiologists can look into heart-related effects, and environmental scientists can track how plastics move through ecosystems and into our bodies. Only through this kind of teamwork can we begin to understand plastic’s full impact on human health now and in the future.

Reference

Alexander J. Nihart, Marcus A. Garcia, Eliane El Hayek et al, Bioaccumulation of microplastics in decedent human brains, nature medicine, Volume 31 , April 2025, 1114–1119, https://doi.org/10.1038/s41591-024-03453-1

2. R. Marfella, F. Prattichizzo, C. Sardu et al, Microplastics and Nanoplastics in Atheromas and Cardiovascular Events, N Engl J Med 2024;390:900-10. DOI: 10.1056/NEJMoa2309822

3. Micronanoplastics found in artery-clogging plaque in the neck, American Heart Association Meeting Report ,  Scientific Conferences & Meetings, Stroke News & Brain Health, 22 April 2025 available from https://newsroom.heart.org/news/micronanoplastics-found-in-artery-clogging-plaque-in-the-neck

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How MIT’s SLIM Microcrystal Injection Technology is Transforming Long-Acting Treatments for HIV and Contraceptives

by with No Comment Research

Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)

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Source: Freepik.com

MIT scientists have developed a self-injectable, long-acting drug delivery system using microcrystals. Learn how this innovation could transform contraception and chronic disease treatment.

Imagine a single injection that lasts for months, delivered through a tiny needle you can use yourself, no surgery, no hospital visit. Thanks to a groundbreaking innovation from researchers at Massachusetts Institute of Technology (MIT), that future is now one step closer.

MIT researchers have introduced a groundbreaking innovation that could make this vision a reality. Called SLIM; Self-aggregating Long-acting Injectable Microcrystals this new drug delivery system offers extended release, smaller needle size, and high drug potency, all packed into a single self-administered injection.

A New Way to Take Medicine: Once Every Few Months

Researchers at MIT and Harvard-affiliated Brigham and Women’s Hospital have developed a new drug delivery system called SLIM, short for Self-aggregating Long-acting Injectable Microcrystals.

Instead of needing large needles or surgery, SLIM allows medicine to be injected just under the skin through a tiny needle. Once injected, the medicine automatically forms a small solid “implant” that slowly releases the drug over several months.

This method is especially promising for medications like birth control and HIV medicine where convenience, privacy, and reliability are essential

Global Health Impact

For millions worldwide especially women in under-served regions SLIM could mean:

No need for surgical implants or repeated clinic visits

Empowered self-administration of essential medications

Lower costs and better access to long-term contraception

This new technology is published in the journal Nature Chemical Engineering. The technology also aligns with public health goals from organizations like the WHO and the study is co-funded by Gates Foundation.

How It Works: Tiny Crystals, Big Impact

SLIM works by suspending drug particles called microcrystals in a liquid. When injected into the body, this liquid mixes with the body’s water and causes the particles to clump together into a compact, slow-dissolving depot.

Less pain, smaller needles: Unlike other long-acting injections that require thick, painful needles, SLIM uses fine needles as small as 30 gauge (about the width of a human hair).

Fewer additives: Most long-acting shots rely on lots of added slowly degrading polymers such as polylactic acid or polycaprolactone to slow down drug release. SLIM only needs a tiny amount, reducing risks of side effects and injection pain.

Why It Matters: Especially for Women and Low-Resource Settings

In many parts of the world, women may not have easy access to clinics for repeated contraception or medications. Self-injectable treatments could empower them to take control of their health privately and conveniently.

This is a big step beyond current injectables like Depo-Provera, which lasts 3 months but can’t match the long-lasting protection of surgical implants like Nexplanon. SLIM offers the best of both: long-lasting protection with no surgery required.

A Breakthrough for Contraceptive Delivery

The researchers tested SLIM using levonorgestrel, a common hormonal contraceptive. In lab studies on rats, the SLIM formulation:

In early tests, the SLIM injection worked really well. After being injected, it formed a small, solid implant under the skin that stayed in place. It released the medicine much more slowly up to 5.6 times slower than current options, helping it last longer. The implant stayed strong and stable for over 3 months, and the injection was easy enough to be done at home using a regular small syringe. This means that women could get fewer injections while still having reliable, long-term birth control.

Bottom Line: Why This Matters for the Future of Medicine

The researchers plan to test SLIM with other drugs, especially those that are hard to dissolve in water, like many modern medications.

They’re also studying how to fine-tune drug release and improve safety for human use.

Because of its compact, stable design, SLIM could become a game-changer for treating chronic conditions like mental health, HIV prevention, or cancer with fewer doses and better adherence.

The SLIM system could redefine how we take medicine offering safer, longer-lasting, and more comfortable treatment through self-administered injections. It’s a promising leap toward better access and better outcomes, especially in global health.

Long-acting injectables are a proven way to boost adherence, especially for chronic conditions. But current systems are limited by: Large, painful needles, Viscous, hard-to-inject formulations and Poor suitability for self-administration.

SLIM overcomes these barriers with smart design: high drug loading, low viscosity, and small injection size all while delivering long-lasting effects.

Reference

Feig, V. R., Park, S., Rivano, P. G., et al. (2025). Self-aggregating long-acting injectable microcrystals. Nature Chemical Engineering, 2(3), 209–219. DOI: 10.1038/s44286-025-00194-x

Engineers develop a better way to deliver long-lasting drugs, MIT News, Massachusetts Institute of Technology, 24 March 2025

Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016 Aug 1;103:144-156. Doi: 10.1016/j.addr.2016.02.003. Epub 2016 Feb 23. PMID: 26916628; PMCID: PMC4935562.

McEvoy, Joseph. (2006). Risks versus benefits of different types of long-acting injectable antipsychotics. The Journal of clinical psychiatry. 67 Suppl 5. 15-8.

National Research Council (US) Committee on Population. Contraception and Reproduction: Health Consequences for Women and Children in the Developing World. Washington (DC): National Academies Press (US); 1989. 4, Contraceptive Benefits and Risks.Available from: https://www.ncbi.nlm.nih.gov/books/NBK235069

 

Source of the Video: Giovanni Traverso (YouTube) _Self-Aggregating Long-Acting Injectable Microcystals

Disclaimer: The video is for educational and informational purposes only.

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Gold Nanoparticles Show Promise for Vision Restoration, Brown University Study Finds

by with No Comment Research

Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)

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Image showing gold nanopracticals undergone surface plasmon resonance after exposure to near infra-red light (NIR) Source: Freepik.Com

Researchers at Brown University have developed a groundbreaking vision restoration method that could help people regain vision loss due to retinal diseases like age-related macular degeneration (AMD) and retinitis pigmentosa. These common causes of vision loss damage the retina the light-sensitive layer at the back of the eye leading to progressive blindness. The innovative approach involves using gold nanoparticles, tiny biocompatible particles that can be safely introduced into the eye. When stimulated by near-infrared (NIR) laser light, these nanoparticles activate the remaining retinal cells, allowing them to send visual signals to the brain much like healthy photoreceptors do. This emerging technology has the potential to outperform existing retinal prosthetics by offering a minimally invasive, less painful alternative that could deliver higher-quality vision restoration. With its promise of improved outcomes, enhanced safety, and greater accessibility, this cutting-edge technique could transform the treatment of retinal degeneration and provide hope for millions living with severe vision impairment or blindness.

The Science behind the Innovation

In healthy eyes, specialized cells called photoreceptors rods and cones detect light and convert it into electrical signals. These signals are then passed to other key retinal cells, such as bipolar cells and ganglion cells, which relay the information to the brain, allowing us to perceive images. However, in degenerative eye diseases like age-related macular degeneration (AMD) and retinitis pigmentosa, these critical photoreceptors degenerate and eventually stop functioning, leading to progressive vision loss and, in severe cases, blindness. Remarkably, the inner retinal cells like bipolar and ganglion cells often remain intact and functional even after the photoreceptors are lost. Building on this insight, researchers at Brown University are developing an innovative vision restoration approach that bypasses the damaged photoreceptors entirely. By using advanced technology to directly stimulate the surviving inner retinal cells, this method could restore vision in individuals affected by retinal degeneration. This novel strategy has the potential to revolutionize vision loss treatment by targeting still-viable parts of the eye, offering a powerful alternative to traditional therapies and retinal implants.

Image Source: Brown University from an article: Golden eyes: How gold nanoparticles may one day help to restore people’s vision. Image Showing: How gold nanoparticles work and how it will create visual image in the mind of patient

The research team at Brown University has developed a cutting-edge technique involving the use of gold nanorods ultra-small, rod-shaped particles made of gold delivered directly into the eye through a minimally invasive procedure called intravitreal injection. These gold nanorods are precisely engineered to absorb near-infrared (NIR) light, a safe and effective wavelength that penetrates deep into the eye without causing damage, since it is minimally absorbed by water in the tissue. Once exposed to NIR light, the gold nanorods undergo a process called surface plasmon resonance, which generates localized and highly controlled heat. This subtle thermal energy can activate surrounding retinal nerve cells in two key ways: by inducing tiny electric currents across their membranes or by triggering specialized ion channels that respond to changes in temperature. This innovative approach offers a promising new method for restoring vision by reactivating the surviving retinal cells in individuals affected by degenerative eye diseases such as macular degeneration and retinitis pigmentosa. It also holds the potential to be a safer, more precise alternative to traditional retinal implants or surgical treatments.

Promising Results in Preclinical Studies

In experimental tests with mice suffering from retinal damage, the research team injected gold nanoparticles into the animals’ eyes and projected patterned near-infrared (NIR) laser light onto the retina. These light patterns, shaped like simple images, were designed to test whether the NIR light could stimulate the remaining healthy retinal cells. Using a powerful technique called calcium imaging; the scientists observed that the bipolar and ganglion cells key players in the visual signalling pathway responded to the laser patterns in a manner similar to how they would react to natural light in a healthy retina. Additionally, brain imaging revealed increased activity in the visual cortex, the region of the brain responsible for processing visual information. This indicated that the brain was once again receiving visual input, a strong sign that sight could potentially be restored. Even more promising, the gold nanoparticles remained stable and safely positioned within the eye for several months, with no signs of toxicity or inflammation. These results highlight the long-term potential of this non-invasive, laser-activated nanoparticle therapy as a safe and effective treatment for restoring vision in people affected by retinal degenerative diseases.

Advantages over Traditional Retinal Prosthetics

This new nanoparticle based method has several key benefits compared to current retinal prosthetic devices. First, it is minimally invasive unlike traditional devices that require complex surgery to implant electrodes; this approach only needs a simple injection into the eye, a common and low-risk procedure in eye care. Second, it offers much higher resolution. Existing devices are limited because they can only stimulate certain fixed spots in the retina, often resulting in blurry or narrow vision. In contrast, the nanoparticles can be targeted more precisely, even down to individual cells, and their stimulation pattern can be changed as needed, potentially restoring a full, detailed field of vision. Lastly, because it uses near-infrared (NIR) light, which doesn’t affect visible light, this method can work alongside any natural vision a person still has, making it a more flexible and user-friendly solution.

Future Outlook

Researchers aim to transform this groundbreaking vision restoration technology into a wearable device, such as smart glasses or high-tech goggles equipped with a camera and a near-infrared (NIR) laser system. The camera would continuously capture visual input from the surrounding environment, while the NIR laser projects precise light patterns onto the retina. These patterns would activate specially designed gold nanoparticles, allowing the user to perceive visual images without the need for invasive procedures. Although more research is needed to confirm long-term safety and effectiveness in larger animal models and eventually in humans, this innovative approach could revolutionize treatment options for millions suffering from retinal diseases and vision loss. By eliminating the need for genetic modification or complex surgical implants, this technology offers a potentially safer, more accessible and cost-effective alternative to current retinal prosthetics, paving the way for broader adoption and improved quality of life for patients worldwide.

Reference:

1. 1.Jiarui Nie, Kyungsik Eom, Hafithe M. AlGhosain, ntravitreally Injected Plasmonic Nanorods Activate Bipolar Cells with Patterned Near-Infrared Laser Projection ACS Nano 2025, 19, 12, 11823–11840, https://doi.org/10.1021/acsnano.4c14061

2. Golden eyes: How gold nanoparticles may one day help to restore people’s vision, 16 April 2025, Brown University.

3. Chen F , Si P , de la Zerda A , Jokerst JV , Myung D . Gold nanoparticles to enhance ophthalmic imaging. Biomater Sci. 2021 Jan 21;9(2):367-390. doi: 10.1039/d0bm01063d. Epub 2020 Oct 15. PMID: 33057463; PMCID: PMC8063223.

4. Natarajan S. Retinitis pigmentosa: a brief overview. Indian J Ophthalmol. 2011 Sep-Oct; 59(5):343-6. Doi: 10.4103/0301-4738.83608. PMID: 21836337; PMCID: PMC3159313.

5. Giuliana Gagliardi, Karim Ben M’Barek, Olivier Goureau, Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: A pluripotent stem cell-based approach, Progress in Retinal and Eye Research, Volume 71, 2019, Pages 1-25, https://doi.org/10.1016/j.preteyeres.2019.03.001

6. Treating retinal disease with tiny gold particles, 24 April 2025, Association of optometrist, available from https://www.aop.org.uk/ot/news/2025/04/24/treating-retinal-disease-with-tiny-gold-particles

7. NEI-funded researchers test new visual prosthesis system to restore vision, 18 April 2025, National Eye Institute, available from https://www.nei.nih.gov/about/news-and-events/news/nei-funded-researchers-test-new-visual-prosthesis-system-restore-vision

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Gut-Brain Connection: Eisenbergiella tayi and Lachnoclostridium Intestinal Bacteria Linked to Multiple Sclerosis

by with No Comment Research

 Medically Reviewed By Vikas Londhe M.Pharm (Pharmacology)

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Source: Freepik.Com

Introduction: A Gut–Brain Connection in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune system mistakenly attacks the central nervous system, which includes the brain and spinal cord. This can lead to a range of symptoms, such as muscle weakness, coordination trouble, and vision or thinking problems. Scientists have known for a while that a person’s genes can play a role in increasing the risk of developing MS. However, in recent years, researchers have started looking closely at the gut microbiome. The vast community of bacteria and other tiny organisms living in our digestive system is a possible environmental factor that could help trigger the disease.

A new study, published in April 2025 in the journal PNAS (Proceedings of the National Academy of Sciences), provides the strongest evidence so far that certain types of gut bacteria might start changes in the body that lead to MS-like illness. This suggests that the microbes in our gut might do more than digest food, as they could also influence serious diseases like MS.

Unique Study Design: Learning from Identical Twins

To better understand how gut bacteria might be involved in multiple sclerosis (MS), researchers studied 81 pairs of identical twins, where only one of the two siblings had MS. Since identical twins share the same genes and usually grow up in very similar environments, this was a smart way to remove other factors and focus just on differences in their gut microbiomes. This helped the scientists look more closely at whether changes in gut bacteria might be related to the start of the disease.

The researchers used a method called 16S rRNA sequencing, which is a powerful tool for identifying and measuring different types of bacteria in the gut. When they compared the bacteria from the twins with MS to their healthy siblings, they found more than 50 types of bacteria (called microbial taxa) that were present in different amounts. One big finding was a noticeable increase in bacteria from a group called the Firmicutes phylum in the twins who had MS. Some of these specific bacteria had already been linked to MS in earlier studies, so this strengthens the idea that they might be involved in triggering or worsening the disease.

Going Deeper: Focusing on the Small Intestine

Most studies on gut bacteria usually analyze stool samples, which come from the large intestine. But this study took a different and more detailed approach. The researchers collected bacteria samples directly from various parts of the intestines, especially a specific area called the terminal ileum this is the last part of the small intestine, located just before the large intestine begins.

Why the terminal ileum? This part of the gut is known to be full of immune system activity, making it a key location where gut bacteria and immune cells closely interact. The researchers believed that certain bacteria living in this region might directly affect how immune cells behave, possibly in a way that could trigger the kind of immune response seen in MS.

By focusing on this area, the study aimed to find out if bacteria here have a stronger or more specific role in influencing the development of MS, compared to bacteria found in the lower parts of the gut

Transferring Human Gut Bacteria to Mice

To find out if the gut bacteria from people with MS could cause disease, the researchers did a special experiment. They took bacteria from the small intestine (specifically the terminal ileum) of the twins who had MS and put them into germ-free mice. These are special mice that are raised in a completely bacteria-free environment and have been genetically engineered to be more likely to develop a disease similar to MS, called EAE (Experimental Autoimmune Encephalomyelitis).

The results were surprising: mice that received bacteria from the MS-affected twins were much more likely to develop EAE compared to mice that received bacteria from the healthy twins. This strongly suggests that the gut microbes from people with MS can trigger disease in animals already genetically vulnerable to it.

Another important discovery: only the female mice got sick. This is especially interesting because MS is much more common in women than in men. So this part of the experiment not only supported the role of gut microbes in disease but also mirrored the gender pattern seen in human MS.

Key Bacteria Identified: The Lachnospiraceae Family

After studying the gut bacteria in the mice that got sick, the researchers were able to pinpoint two specific types of bacteria that seemed to play a big role: Eisenbergiella tayi and Lachnoclostridium. These bacteria belong to a larger group called the Lachnospiraceae family.

What’s interesting is that these bacteria are usually found in very small amounts in stool samples, so they had not received much attention in earlier studies. But in this study, they showed up clearly because the researchers sampled the small intestine, not just faeces.

In the mice that developed MS-like disease, these two species didn’t just appear they grew rapidly and took over large parts of the gut. Even more important, their presence was linked to changes in the immune system. Specifically, the mice had more inflammatory Th17 cells, which are a type of immune cell known to cause damage in MS. This suggests that these gut bacteria may be directly encouraging harmful immune activity that leads to the disease.

Why the Ileum Is Important

The small intestine, and especially a section called the ileum, plays a very important role in how the immune system learns to tell the difference between harmless and harmful substances. This part of the gut contains special immune structures called GALT (gut-associated lymphoid tissue). In this area, immune cells are constantly interacting with the bacteria and other microbes that live in the gut.

The researchers believe that the bacteria Eisenbergiella tayi and Lachnoclostridium may take advantage of this environment. These microbes could influence immune cells in the ileum in a harmful way, possibly by:

Molecular mimicry – this is when bacteria have molecules on their surface that look like parts of the body’s own cells. This can confuse the immune system and cause it to attack healthy tissue.

Inflammatory signalling – this means the bacteria might release substances that cause the immune system to become overactive or inflamed.

Either way, these interactions could activate T cells, a type of immune cell, and cause them to become autoimmune, meaning they start attacking the body’s nervous system, which is what happens in MS.

Why Females Were More Affected

One of the most interesting findings from the study was that only the female mice developed MS-like disease after receiving the gut bacteria from people with MS. This matches what we see in humans MS is about two to three times more common in women than in men.

The exact reason for this difference isn’t fully understood yet, but scientists think it may have to do with how female hormones or the female immune system interacts with certain bacteria. It’s possible that women’s bodies respond more strongly to gut bacteria that trigger inflammation, which could increase the chances of developing MS.

This part of the research highlights that sex differences may play a key role in how diseases like MS develop, especially when gut microbes are involved.

What This Could Mean for Future MS Treatments

If these findings are confirmed by more research, they could open the door to new ways of treating MS by focusing on the gut microbiome especially the harmful bacteria that may trigger the disease.

For example, future treatments might include:

Targeted probiotics (helpful bacteria) to crowd out the bad ones

Special antibiotics that remove only the harmful bacteria, like E. tayi and Lachnoclostridium

Diet changes that support a healthier gut and reduce inflammation

A New Approach to Understanding MS and Other Autoimmune Diseases

One important lesson from this study is the new method it used to analyze the gut bacteria. Instead of just looking at stool samples, which come from the large intestine, the researchers focused on bacteria taken directly from the small intestine. This is a big deal because it gives scientists a more detailed view of the gut microbiome and its role in diseases like MS.

This approach could be very helpful for studying other autoimmune diseases as well, not just MS. By analyzing the bacteria in different parts of the gut, researchers could get a better understanding of how these diseases develop and find more accurate ways to diagnose them. It might even lead to personalized treatments based on the unique microbiome of each patient.

Conclusion: A New Chapter in MS Research

This study marks a big step forward in understanding how gut bacteria might actually help cause multiple sclerosis (MS) not just be connected to it. By using a careful approach that included identical twin studies and germ-free mice experiments, the researchers were able to do more than just find suspicious bacteria. They showed that these microbes could trigger MS-like disease in the right conditions.

This research adds to the growing evidence of a strong link between the gut and the brain known as the gut–brain axis. As scientists continue to learn more about this connection, we may soon see new, safer, and more targeted treatments that work by adjusting gut bacteria. This could lead to better ways to prevent or manage autoimmune diseases like MS in the future.

References:

1.Altieri C, Speranza B, Corbo MR, Sinigaglia M, Bevilacqua A. Gut-Microbiota, and Multiple Sclerosis: Background, Evidence, and Perspectives. Nutrients. 2023 Feb 14;15(4):942. Doi: 10.3390/nu15040942. PMID: 36839299; PMCID: PMC9965298.

2. Hongsup Yoona, Lisa Ann Gerdesa , Florian Beigel et al, Multiple sclerosis and gut microbiota: Lachnospiraceae from the ileum of MS twins trigger MS-like disease in germfree transgenic mice—An unbiased functional study, PNAS  2025  Vol. 122  No. 18 e2419689122, https://doi.org/10.1073/pnas.2419689122

3. Thirion, F., Sellebjerg, F., Fan, Y. et al.The gut microbiota in multiple sclerosis varies with disease activity. Genome Med15, 1 (2023). https://doi.org/10.1186/s13073-022-01148-1

4. Vinod K. Gupta h Guneet S. Janda, Heather K. Pump  Nikhil Lele et al, Alterations in Gut Microbiome-Host Relationships After Immune Perturbation in Patients With Multiple Sclerosis, Neurology: Neuroimmunology & Neuroinflammation | Volume 12, Number 2 | March 2025

5. Correale, J., Hohlfeld, R. & Baranzini, S.E. The role of the gut microbiota in multiple sclerosis. Nat Rev Neurol18, 544–558 (2022). https://doi.org/10.1038/s41582-022-00697-8

6. Hindson, J. A possible link between multiple sclerosis and gut microbiota. Nat Rev Neurol13, 705 (2017). https://doi.org/10.1038/nrneurol.2017.142