Written by: Shital Gaikwad M.Pharm (Pharmacology)
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.
Source: The Children’s Hospital of Philadelphia (YouTube)
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
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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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