Sarepta’s SRP-1003 Achieves Up to 80% Nuclear DMPK RNA Knockdown in Preclinical DM1 Studies

Sarepta Therapeutics presented new preclinical data on SRP-1003, its investigational small interfering RNA (siRNA) program for myotonic dystrophy type 1 (DM1), at the 22nd Annual Meeting of the Oligonucleotide Therapeutics Society (OTS). Reported on October 14, 2026, the findings showed dose-dependent reductions of up to approximately 80% in pathogenic DMPK messenger RNA (mRNA) in both the nucleus and cytoplasm of DM1 patient-derived muscle cells. The results address a central challenge for DM1-directed RNA therapies: reducing toxic transcripts that accumulate within the nucleus.

DM1 Biology and SRP-1003

DM1 is the most common form of adult-onset muscular dystrophy. It is caused by a CTG repeat expansion in the DMPK gene, which produces toxic CUG-repeat RNA transcripts. These transcripts accumulate in the nucleus and sequester muscleblind-like (MBNL) proteins, disrupting RNA splicing across multiple tissues, including skeletal muscle and the heart. No disease-modifying treatment is currently approved for DM1.

SRP-1003 is designed to silence DMPK mRNA using an αvβ6 integrin-targeted siRNA platform intended to deliver the therapy to muscle. Because toxic RNA accumulation and MBNL-dependent splicing abnormalities occur in the nucleus, demonstrating nuclear target engagement is important to establishing whether the approach addresses the disease-associated molecular pathology.

Nuclear and Cytoplasmic DMPK Knockdown

In DM1 patient-derived myotubes, SRP-1003 produced dose-dependent reductions in DMPK mRNA in both nuclear and cytoplasmic compartments, reaching approximately 80% knockdown in each. Compartment-fractionated digital droplet polymerase chain reaction (ddPCR) was used to quantify the transcripts, with established RNA controls supporting the purity of the nuclear and cytoplasmic fractions. A scrambled siRNA control did not produce the same knockdown, supporting the specificity of the observed effect.

Sarepta also reported three complementary methods supporting nuclear target engagement: compartment-fractionated ddPCR, RNA fluorescence in situ hybridization (RNA FISH) to quantify toxic RNA foci, and in situ RNAscope in intact cells.

Effects on Toxic RNA Foci and Abnormal Splicing

SRP-1003 reduced toxic nuclear RNA foci in patient-derived myotubes. In the DMSXL mouse model of DM1, treatment also reduced nuclear RNA foci in skeletal muscle, diaphragm and myocardium, alongside significant reductions in human and mouse DMPK mRNA.

In a second mouse model expressing a pathogenic human DMPK transgene, a surrogate siRNA for SRP-1003 reduced nuclear pathogenic DMPK RNA and produced dose-dependent correction of MBNL-dependent mis-splicing, assessed by RNA sequencing. This correction provides functional evidence consistent with nuclear target engagement, complementing the direct measurements of RNA reduction.

Preclinical Muscle Exposure

In separate pharmacokinetic studies, SRP-1003 remained detectable across multiple muscle groups for up to 16 weeks following a single intravenous dose in preclinical models. This finding supports prolonged tissue exposure but does not establish that DMPK knockdown or functional effects persisted throughout that period.

Clinical Development and Safety Context

SRP-1003 is being evaluated in SRP-1003-101, a first-in-human, Phase 1/2, randomized, placebo-controlled study involving single and multiple ascending doses in adults aged 18 to 65 years with DM1. Sarepta reported preliminary clinical findings from the first cohort earlier in 2026, including dose-dependent muscle exposure and an early DMPK biomarker signal. These findings require interpretation in light of the small early-stage dataset.

One fatal cardiac arrhythmia occurred during the study. According to the company’s reported assessment, the investigator, sponsor and independent coroner considered the event unrelated to SRP-1003 and consistent with the known cardiac risks of DM1. This reported assessment does not remove the need for continued safety evaluation as clinical exposure increases. Sarepta expects to report further clinical results later in 2026.

Clinical Interpretation

The preclinical findings strengthen the biological rationale for SRP-1003 by combining direct measurements of nuclear DMPK RNA reduction with evidence of reduced toxic RNA foci and correction of abnormal splicing. However, these results do not establish clinical benefit. Further clinical data will need to determine whether DMPK reduction translates into meaningful improvements in myotonia, muscle function, cardiac conduction and quality of life.

References

Sarepta Therapeutics. Sarepta Therapeutics Presents New Preclinical Data Demonstrating Robust Knockdown of Pathogenic DMPK RNA in the Nucleus with SRP-1003 in DM1 at 2026 Oligonucleotide Therapeutics Society Annual Meeting. October 14, 2026.

Preclinical Evaluation of SRP-1003: An αvβ6 Integrin-Targeting siRNA for Nuclear-Targeted Knockdown of DMPK in Myotonic Dystrophy Type 1, Presented at the 22nd annual meeting of the oligonucleotide therapeutics society (OTS); October 11-14, 2026; Denver, CO