Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy affecting 1 in 3500 to 5000 boys at birth globally. Patients experience a progressive wasting of both skeletal and cardiac muscles attributable to the loss of dystrophin protein encoded by the DMD gene on chromosome Xp21. The milder symptoms in Becker muscular dystrophin (BMD) patients, who have an in-framed truncated but still functional dystrophin protein, provide a hereditary basis for exon skipping therapy against DMD.
GEN6050X is a clinical investigational drug which utilized Targeted AID-mediated Mutagenesis (TAM) cytosine base editor (CBE) to induce DMD exon 50 skipping via editing the 5’SS of human DMD IVS50. GEN6050X is an intravenous dual AAV product containing two AAV9 drug products. One encodes muscle-specific promoter-driven TAM CBE protein while the other encodes 3 copies of hE50 sgRNA targeting human DMD IVS50 5’SS. Additionally, the sgRNA vector carries a human gamma-actin gene, which can bind de novo dystrophin to rapidly facilitate costamere and dystroglycan-associated complex remodeling and provide a synergistic therapeutic effect.
Single dose of GEN6050X i.v to 21-day-old humanized Dmd mouse model DmdhE50delE51 greatly restored dystrophin protein expression in heart and skeletal muscles. Correspondingly, GEN6050X treatment significantly improved the muscle function and histopathology in both heart and skeletal muscles of DmdhE50delE51 mice. No high-risk sgRNA-dependent or independent DNA off targets, chromosome structure variation and transcriptome off targets were found in vitro.
In 26 weeks of cynomolgus monkey toxicology study, minimal liver toxicity was observed at Week 13 while liver toxicity was resolved at Week 26 in both 5E13vg/kg and 2E14vg/kg GEN6050X group. The Highest Non-Severely Toxic Dose (HNSTD) was identified as 2E14vg/kg in NHP.
An IIT study was initiated in Oct 2024 to evaluate the safety and tolerability of GEN6050X (NCT06392724). Two patients have received 5E13vg/kg GEN6050X till November 2024. The first patient has finished 3-month follow-up. The safety profile is good. The first muscle biopsy will be conducted in Feb 2025. All clinical manufacture has been finished, and IND filing will be expected at the end of 2024.
Collectively, GEN6050X is a safe and effective gene editing drug candidate and may provide a cure for DMD exon 50 skipping patients.