CAMBRIDGE, Mass., October 14, 2026
Sarepta Therapeutics, Inc. (NASDAQ: SRPT) presented new preclinical data demonstrating that its investigational small interfering RNA (siRNA) therapy SRP-1003 can reduce disease-causing DMPK RNA in both the nucleus and cytoplasm in models of myotonic dystrophy type 1 (DM1). Presented at the 22nd Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), the findings showed dose-dependent reductions of up to approximately 80% in pathogenic DMPK messenger RNA (mRNA) in each cellular compartment. The research also demonstrated correction of muscleblind-like (MBNL)-dependent RNA mis-splicing, providing functional evidence that SRP-1003 reduces toxic RNA within the nucleus, where key molecular processes underlying DM1 occur. Nuclear target engagement was supported by three complementary methods: compartment-fractionated digital droplet polymerase chain reaction (ddPCR), RNA fluorescence in situ hybridization (RNA FISH), and RNAscope. Additional preclinical pharmacokinetic studies showed that SRP-1003 remained detectable across multiple muscle groups for up to 16 weeks after a single intravenous dose. The company said these findings strengthen the biological rationale for advancing SRP-1003, which is currently being evaluated in an ongoing Phase 1/2 clinical study.
SRP-1003 Demonstrates Dose-Dependent DMPK RNA Reduction
The preclinical findings address a central challenge in developing treatments for DM1: reducing the toxic RNA transcripts responsible for the disease’s molecular effects. DM1 is caused by a CTG repeat expansion in the DMPK gene, which leads to the accumulation of toxic CUG-repeat RNA in the nucleus. These transcripts trap MBNL proteins and disrupt normal RNA processing, or splicing, across numerous genes. Because MBNL sequestration and the affected splicing processes occur in the nucleus, demonstrating activity in this compartment is important to the therapeutic approach. In DM1 patient-derived muscle cells, known as myotubes, compartment-fractionated ddPCR directly measured DMPK mRNA in nuclear and cytoplasmic transcript pools. SRP-1003 produced dose-dependent reductions in both compartments, achieving up to approximately 80% knockdown in each, with nuclear activity comparable to cytoplasmic activity. The researchers validated compartment purity using established nuclear and cytoplasmic RNA controls. The reduction was specific to SRP-1003 and was not observed with a scrambled siRNA control. These findings suggest that the investigational therapy can reach and reduce its intended RNA target within the nucleus in the tested preclinical systems. However, the reported knockdown results are preclinical findings and do not establish clinical benefit in people with DM1.
Three Methods Support Nuclear Target Engagement
Sarepta reported that three independent and complementary methodologies supported the evidence of nuclear activity. Compartment-fractionated ddPCR quantified DMPK transcripts separately in nuclear and cytoplasmic fractions, while RNA FISH quantified toxic nuclear RNA foci in patient-derived myotubes. The company also used RNAscope, an in situ RNA detection method, to examine target engagement in intact cells. In the DMSXL mouse model of DM1, treatment reduced nuclear RNA foci in skeletal muscle, diaphragm and myocardium and was associated with significant reductions in both human and mouse DMPK mRNA. In a separate mouse model expressing a pathogenic human DMPK transgene, a surrogate siRNA designed to represent SRP-1003 reduced pathogenic human DMPK RNA in the nucleus. Researchers also observed dose-dependent correction of MBNL-dependent mis-splicing, assessed through RNA sequencing. This correction provides a functional measure of nuclear activity because the disease-associated RNA disrupts MBNL function and RNA splicing within the nucleus. Sarepta’s President of Research & Development and Technical Operations, Louise Rodino-Klapac, Ph.D., said the combined findings provide complementary evidence of nuclear target engagement and support continued development of SRP-1003. The results were presented in poster P-066, “Preclinical Evaluation of SRP-1003: An αvβ6 Integrin-Targeting siRNA Platform for Targeted Knockdown of DMPK in Myotonic Dystrophy Type 1.”
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Sustained Muscle Exposure and Ongoing Clinical Evaluation
Separate preclinical pharmacokinetic studies found that SRP-1003 remained detectable across multiple upper- and lower-body muscle groups for up to 16 weeks following a single intravenous dose. The finding provides information about the therapy’s persistence in muscle tissues in the tested models, although it does not establish how long its effects will last in patients or determine an appropriate clinical dosing schedule. SRP-1003 is an investigational siRNA therapy designed to silence DMPK mRNA in target cells. Sarepta is evaluating the candidate in Study SRP-1003-101, a first-in-human Phase 1/2 randomized, placebo-controlled trial using single ascending dose and multiple ascending dose designs. The study is enrolling adults with DM1 aged 18 to 65. According to the company, results from the ongoing clinical study are expected later in 2026. DM1 is a progressive, multisystem disorder that can affect skeletal and smooth muscle, the heart, respiratory function, vision, endocrine and gastrointestinal systems, and the central nervous system. Symptoms can include muscle weakness, daytime sleepiness, breathing difficulties and cardiac conduction abnormalities. There is currently no cure for DM1, and the company states that no disease-modifying treatments are available. The clinical program will be important for determining whether the molecular effects observed in preclinical models translate into safety, target engagement and meaningful clinical outcomes in people with the disease.
Source::Sarepta Therapeutics,, press release
