Correction of MBNL- dependent mis-splicing provides functional evidence that SRP-1003 is degrading disease-causing RNA within the nucleus.
In a preclinical model, SRP-1003 reduced pathogenic DMPK mRNA in both the cytoplasm and nucleus in a dose-dependent manner, achieving up to approximately 80% knockdown in each compartment
Nuclear target engagement supported by three independent methodologies, including compartment-fractionated ddPCR, RNA FISH, and RNAscope
SRP-1003 remained detectable across multiple muscle groups for up to 16 weeks following a single intravenous dose

Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today presented new preclinical data at the 22nd Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) demonstrating that SRP-1003, the company's investigational small interfering RNA (siRNA) program for the treatment of myotonic dystrophy type 1 (DM1), can directly reduce pathogenic DMPK transcripts within the nucleus, where the molecular drivers of DM1 pathology originate.

In the analysis, correction of muscleblind-like (MBNL)-dependent mis-splicing provide functional evidence of nuclear activity. Direct measurement of the nuclear and cytoplasmic transcripts pools further demonstrated the efficiency of that activity, with SRP-1003 producing comparable, dose-dependent DMPK in both compartments and achieving up to approximately 80% knockdown in each. The results were confirmed via three independent and complementary methods: RNA fluorescence in situ hybridization (FISH) foci quantification, compartment-fractionated ddPCR with purity controls, and in situ RNAscope in intact cells.

DM1 is caused by a CTG repeat expansion in the DMPK gene that leads to the buildup of toxic CUG-repeat RNA transcripts within the nucleus. This toxic RNA traps MBNL proteins and disrupts the normal processing, or splicing, of many other RNAs, leading to disease across multiple organ systems. Since both MBNL sequestration and pre-mRNA splicing occur in the nucleus, correcting MBNL mis-splicing is functional evidence that the therapy has reached and reduced the disease-causing RNA in the nucleus.

"For an siRNA approach to address the underlying biology of DM1, it must reduce the toxic DMPK in the nucleus," said Louise Rodino-Klapac, Ph.D., president, Research & Development and Technical Operations, Sarepta. "These results provide two complementary lines of evidence that SRP-1003 effectively and efficiently gets into the nucleus. We observed correction of MBNL-dependent mis-splicing, a functional readout that requires degradation of the nuclear transcript and measured comparable levels of DMPK knockdown in the nucleus and cytoplasm. Together with the reductions in toxic nuclear RNA foci across multiple models and methods, these data strengthen the biological rationale for SRP-1003 and support the continued advancement of the program in our ongoing Phase 1/2 clinical study, from which we expect to share results later this year."

Details from the SRP-1003 poster presentation:

P-066: Preclinical Evaluation of SRP-1003: An αvβ6 Integrin-Targeting siRNA Platform for Targeted Knockdown of DMPK in Myotonic Dystrophy Type 1 (C. Greer, et al.)

In DM1 patient-derived myotubes, compartment fractioned ddPCR directly measured DMPK mRNA in the nuclear and cytoplasmic transcript pools. SRP-1003 produced dose dependent reductions in both compartments, achieving up to approximately 80% knockdown in each, with nuclear knockdown comparable to cytoplasmic knockdown. Fractional purity was validated using established cytoplasmic and nuclear RNA controls, and DMPK knockdown was specific to SRP-1003 and was not observed with a scrambled siRNA control.

SRP-1003 also reduced toxic nuclear RNA foci in patient-derived myotubes, as demonstrated by RNA fluorescence in situ hybridization (RNA FISH). 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 second DM1 mouse model expressing a pathogenic human DMPK transgene, an SRP-1003 surrogate siRNA reduced pathogenic human DMPK RNA in the nucleus and produced dose-dependent correction of MBNL-dependent mis-splicing as assessed by RNA sequencing.

This splicing correction is an important functional readout of nuclear activity: because the trapped MBNL proteins and the affected splicing machinery are located in the nucleus, the observed correction indicates that the disease-causing nuclear RNA was degraded rather than only in the cytoplasm.

In separate pharmacokinetic studies, SRP-1003 demonstrated sustained exposure across multiple upper and lower body muscle groups for up to 16 weeks following a single intravenous dose in preclinical models.

About DM1 and SRP-1003

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy and is caused by a repeat expansion in the DMPK gene. DM1 is a progressive, multisystem disorder that affects skeletal and smooth muscle, as well as the heart, respiratory system, eye, endocrine, gastrointestinal, and central nervous systems. The disease is commonly associated with muscle weakness, daytime sleepiness, breathing difficulties, and cardiac conduction abnormalities. There is currently no cure for DM1, and no disease modifying treatments are available.

SRP-1003 is an investigational siRNA treatment for DM1 and is designed to target and knockdown, or silence, the DMPK mRNA in target cells. SRP-1003 is currently being studied in a first-in-human, Phase 1/2, single ascending dose (SAD)/multiple ascending dose (MAD), randomized, placebo-controlled clinical trial (Study SRP-1003-101) that is being conducted in individuals with DM1 aged 18 to 65.

About Sarepta Therapeutics

Sarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. We hold a leadership position in Duchenne muscular dystrophy (Duchenne) and are building a robust portfolio of programs across muscle, central nervous system, and cardiac diseases. For more information, please visit www.sarepta.com or follow us on LinkedIn, X, Instagram and Facebook.

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