In-vivo Validation of HG004 Gene Replacement Therapy for Inherited Blindness

Abstract

Purpose : Mutations in the RPE65 gene block the visual cycle, resulting in a congenitally inadequate supply of chromophores to rod- and cone-photoreceptors. We developed an AAV9 gene replacement therapy carrying the human RPE65 gene, HG004, and evaluated it in treating RPE65-associated inherited retinal dystrophy (RPE65-IRD).

Methods : The 1- or 10-month-old Rpe65-deficient mice were subretinally injected with either HG004 or vehicle control. Efficacy was evaluated through optical coherence tomography, electroretinography, and histochemical staining. We also conducted a toxicology study of bilateral injection at 3 doses of HG004 in NHPs and performed clinical observation, ophthalmic examinations, vector shedding/biodistribution, and immunogenicity assessments at different termination points.

Results : HG004 demonstrated a significant recovery in scotopic b-wave responses in all treated groups compared to the control group of Rpe65^-/- mice injected with a vehicle (p<0.01). The restoration ratio reached over 60% of the wild-type (WT) level and was sustained for 34 weeks. The retinal thickness of HG004-treated and untreated eyes in Rpe65^-/- mice were 85% and 67% of the WT level, respectively. The ERG amplitude recovery in treated eyes of 10-month-old Rpe65^-/- mice was 38.7% of the WT mice at the same age, and the retinal thickness of treated eyes was 62% of the WT level while the untreated eyes exhibited only 53%. The distribution of HG004 was mainly in retina tissues with no detection in the reproductive system and no drug-related systemic toxicity was observed at 4- and 13-week post-injection in NHPs. Adverse events were primarily observed in the retinas of all tested groups of NHPs, suggesting that the injection procedure mainly caused these events (Figure1). Immunotoxicity assessments also revealed no drug-related abnormalities with no immune response of AAV or RPE65 antigen-specific T cells in NHPs.

Conclusions : Our findings highlight the significant therapeutic potential of HG004 in restoring the function of RPE and photoreceptor cells with durability for at least 34 weeks in Rpe65^-/- mice. Furthermore, our toxicology results in NHPs indicate that HG004 is well-tolerated with a good safety profile. These results strongly support the potential benefit of HG004 in treating RPE65-IRD. HG004 IND has been cleared by the U.S. FDA and China CDE and is currently being investigated in humans.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.