Facioscapulohumeral muscular dystrophy (FSHD) is a devastating, incurable genetic muscular disorder that affects approx. 1 million individuals worldwide.
Two disease subtypes exists, FSHD1 and FSHD2. FSHD1 accounts for about 95% of all cases and arises through epigenetic changes in the D4Z4 repeat region on chromosome 4. This leads to activation of the double homeobox protein 4 gene (DUX4) (which is normally transcriptionally repressed), resulting in the expression of proteins that damage muscles. Over time, the affected muscles become weak and atrophic. FSHD is the third most common type of muscular dystrophy after Duchenne and Becker muscular dystrophies and myotonic dystrophy.
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Facioscapulohumeral muscular dystrophy (FSHD) affects approx. 1 million individuals worldwide.
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A Phase 1/2 Open-label Dose-escalation Study to Evaluate the Safety, Tolerability, and Biological Activity of EPI-321, an AAVrh74-delivered Epigenetic Editing Therapy in Adult FSHD Patients
EPI-321 is an investigational drug product comprising a recombinant adeno-associated viral vector, serotype rh74 (AAVrh74), for the delivery of genetic material encoding an epigenetic editor designed to address the root case of FSHD. AAVrh74 has been shown to transduce human skeletal muscle efficiently in the clinical experience. EPI-321's transgene product, a non-cutting, nuclease-dead mini, clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein (dCasONYX) with fuse epigenetic modulators, is designed to selectively bind the D4Z4 repeat region via the accompanying guide RNA, methylate CpG groups within the region near the DUX4 gene on chromosome 4q35, and thus repress the expression of toxic DUX4 protein, ameliorating the downstream pathology that drives FSHD. As it is under a muscle-specific promoter, the dCasONYX-fused protein is expected to be preferentially and actively expressed in muscle tissue following a single intravenous (IV) dose.
EPI-321-02 clinical trial is an open label dose ascending study of EPI-321 for safety and tolerability to determine the best dose for a future trial of drug activity. Two dose levels will be evaluated. In addition, this study will collect secondary outcome data on muscle function, imaging characteristics, and other markers of disease activity at the baseline and throughout the study to assess their utility as measures of drug activity in a future clinical trial.
