Clinical and Molecular Features of CNGA1-Associated Retinitis Pigmentosa in an East Asian Cohort: Insights for Gene Therapy Trials.

PURPOSE: To characterize the natural history of CNGA1-associated retinitis pigmentosa (RP) in an East Asian cohort and to identify potential endpoints for clinical trials.

DESIGN

A multicenter, retrospective cohort study.

PARTICIPANTS

Patients diagnosed with CNGA1-associated RP.

METHODS

Medical records were reviewed for age at onset, symptoms, best-corrected visual acuity, ultra-widefield retinal imaging, spectral-domain OCT, full-field electroretinography, full-field stimulus threshold (FST), multiluminance mobility testing (MLMT), and static perimetry.

MAIN OUTCOME MEASURES: Molecular genetic findings, visual acuity decline rate, FST measurements, MLMT score, retinal sensitivity, and image findings.

RESULTS

The cohort included 57 patients (mean age 42 ± 16 years). Eighteen disease-causing CNGA1 variants were identified, 11 of which were novel. The c.253delC variant was the predominant mutation in both the Chinese and Korean cohorts, with an allele frequency of 69%. A fundus autofluorescence (FAF) staging system was applied to stratify disease severity. Despite high prevalence of epiretinal membranes (57.9% of eyes) and inner-retinal cysts (26.3% of eyes), OCT imaging demonstrated long-term preservation of the foveal ellipsoid zone until stage 4, indicating a broad therapeutic window. Best-corrected visual acuity decline was minimal and varied across stages, whereas cataracts in the fourth to fifth decades significantly impaired visual acuity, with 70% presenting as anterior subcapsular cataract. Multiluminance mobility testing showed a ceiling effect among potential trial candidates (stages 1-3). The decline rate of mean deviation in static perimetry was 0.17 dB per year. The estimated number of progression loci (≥7 dB decline) across the central field was 5.83 over 1 year, supporting the ability to meet US Food and Drug Administration thresholds for clinical meaningful change. Full-field stimulus threshold showed a cone-mediated pattern across different stages but remained valuable for detecting rod functional restoration.

CONCLUSIONS

CNGA1-associated RP in East Asians is characterized by a rod-cone dystrophy phenotype with a broad therapeutic window. The FAF-based staging system provides a reliable framework for severity assessment and reveals stage-specific progression patterns, with no significant genotype-phenotype association observed. The high prevalence of the c.253delC variant suggests that gene editing is a promising therapeutic strategy alongside gene augmentation. Static perimetry appears to be the most promising primary endpoint for future clinical trials.

FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.