Safety and Vision Outcomes Following Gene Therapy for Bietti Crystalline Dystrophy: A Nonrandomized Clinical Trial.

Importance: Bietti crystalline dystrophy (BCD) is a severe genetic retinopathy caused by variants in the CYP4V2 gene. Currently, there is no approved treatment for BCD. Objective: To evaluate safety and vision outcomes following gene therapy with adeno-associated virus (AAV) encoding CYP4V2 (rAAV-hCYP4V2, NGGT001 [Next Generation Gene Therapeutics]). Design, Setting, and Participants: This open-label, dose-escalation nonrandomized clinical trial was conducted from February 2023 to May 2024 at 2 study sites in China. Patients with genetically confirmed biallelic disease-linked CYP4V2 variants received subretinal injections of rAAV2-hCYP4V2 at 1 of 2 dosage levels and were followed up for 12 months. Intervention: A single unilateral injection of 1.5 × 1011 or 3.0 × 1011 total vector genomes of recombinant AAV-hCYP4V2 in the worse eye, based on visual acuity letter score. Main Outcomes and Measures: The primary outcome was safety, assessed by clinical examination of ocular inflammation and evaluated by routine clinical chemistry and immunogenicity testing. Secondary outcomes were changes in visual function from baseline in best-corrected visual acuity (BCVA), microperimetry, and contrast sensitivity 12 months after treatment. Results: Among 12 patients with BCD (6 patients per dose group), mean (SD) patient age was 40.5 (7.1) years, and 5 patients (42%) were female. No severe adverse events related to the treatment were observed. However, mild intraocular inflammation was noted in 1 participant. The median (IQR) baseline BCVA letter score for the study eye was 34 (10-53), equivalent to 20/200 Snellen, while the nonstudy eye had a median (IQR) BCVA of 60 (40-67), equivalent to approximately 20/63 Snellen. At 12 months, the study eye improved by a mean (SD) letter score of 13.9 (13.1) compared with 6.3 (7.4) in the nonstudy eye. The 12-month median (IQR) BCVA for the study eye was 53 (37-64) (equivalent to approximately 20/80 Snellen) and 62 (42-70) (approximately 20/50 Snellen) for the nonstudy eye. Conclusions and Relevance: This open-label, exploratory nonrandomized clinical trial identified no serious safety concerns related to gene therapy over 12 months' follow-up among patients with BCD. While improvement in BCVA was noted, the magnitude was within test-retest values typically noted in eyes with very low levels of visual acuity, and BCVA improvement in both the study and nonstudy eyes could be related to a learning effect, with greater improvement in the study eye possibly related to study eyes' being the worse-seeing eye. Trial Registration: ClinicalTrials.gov Identifier: NCT06302608.