Safety and Efficacy of AAV-Mediated Gene Replacement Therapy in Bietti Crystalline Corneoretinal Dystrophy (BCD) Patients with CYP4V2 mutations

Abstract

Purpose : BCD is an autosomal recessive inherited retinal disease (IRD) caused by mutations in the CYP4V2 gene, which is a blindness-causing disease and a relatively common cause of IRDs in east Asian populations. We report the preliminary safety and efficacy results from a first-in-human gene therapy clinical trial with BCD patients. This study is registered with ClinicalTrials.gov, number NCT04722107.

Methods : Six subjects with genetically confirmed biallelic mutation in CYP4V2 and clinically diagnosed with BCD were enrolled. All subjects received recombinant adeno-associated virus that contains the gene for human CYP4V2 protein (rAAV2/8-hCYP4V2) by single subretinal administration with 150µL volume of drug at a dose of 7.5×10¹⁰ viral genomes (vg).

Results : Three subjects were followed up for more than 1 year, while another 3 subjects had an over 6 months follow-up. We tested immunogenicity by measuring CYP4V2 antibody, rAAV8 capsid neutralizing antibody, rAAV8 capsid binding antibody, as well as T-cell immune response against rAAV vector and CYP4V2 protein. To date, they did not demonstrate systemic immune reactions. All 6 subjects experienced 13 adverse events (AEs) in total, of which 2 were serious adverse events (SAEs) (table). No drug related SAEs were observed to date, which showed preliminarily favorable drug safety. The best-corrected visual acuity (BCVA) (ETDRS chart) results of the three without procedural injury have a significant improvement with an average increase of 14.5 letters. The visual acuity improved 2 weeks after administration and remained stable after 4 weeks (Figure). The multi-luminance mobility test (MLMT) showed that the scores of 5 subjects were improved. The scores of total 6 subjects increased by about 1.17 in average. These encouraging improvements of vision function scores indicate some early efficacy of the gene therapy product.

Conclusions : Early safety and efficacy signals suggest positive clinical benefits of the gene replacement therapy in BCD Patients with CYP4V2 mutations. More subjects, long-term observation and more detailed analysis to the results are needed.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Table Adverse Events of Subjects

 

Figure Changes in BCVA Relative to Natural History in Subjects Without Procedural Injury