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Natural history study of CNGB3-associated achromatopsia (ACHM) shows that residual cone function in affected patients is highly variable

A natural history study of patients with CNGB3-associated achromatopsia has shown considerable variance in the density of functioning cone cells in patients with the disorder. The study, conducted as a collaboration between Applied Genetic Technologies Corporation (NASDAQ: AGTC), a biotechnology company, and the Medical College of Wisconsin (MCW), was aimed at defining the phenotype of patients that may be recruited to clinical studies for potential gene therapy treatments. The multi-center study assessed residual foveal cone structure in 51 genetically confirmed patients with ACHM caused by mutations in the CNGB3 gene. Findings from OCT, confocal AOSLO, and split-detection AOSLO showed that peak foveal cone density ranged from 7,273 to 53,554 cones/mm2, significantly lower than the normal range (84,733–234,391 cones/mm2). As cones represent the therapeutic target for a number of gene therapy treatments, the degree of residual cone structure may serve as a “predictor for therapeutic potential” in ACHM patients.


Congenital achromatopsia (ACHM) is a rare disorder inherited in an autosomal recessive manner affecting cone signal transduction in approximately 1 in 30,000 people globally. Symptoms of the disorder include low visual acuity, photo aversion, nystagmus and impaired chromatic discrimination, while the rods remain largely unaffected, in essence, the opposite of retinitis pigmentosa. The disease has been associated with a mutation in one of six genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), with CNGA3 and CNGB3 mutations accounting for approximately 70% of all ACHM cases. Considerable progress has been made in recent years regarding experimental gene therapies applied to ocular disorders and a critical component for the testing of such novel therapies is a sound understanding of the natural course of the disease and an understanding of the rate of cone cell loss as the disease progresses. The current study focused on the CNGB3 population of ACHM patients as an open label Phase I/II clinical trial in this group is currently aiming to recruit approximately 24 patients (NCT02599922) and is expected to deliver initial results sometime in 2017/18.


Commenting on the publication of the natural history data in the journal IOVS (DOI:10.1167/ iovs.16-19313), Joseph Carroll, PhD, co-director of the Advanced Ocular Imaging Program, MCW stated, “patients living with achromatopsia today have no effective treatment options, but a growing body of evidence suggests that emerging gene therapies may have significant potential. Current data show significant variation in the degree of residual cone photoreceptor structure among patients with CNGB3-associated ACHM. As such, imaging tools that can accurately quantify the remaining cone population may aid in selecting patients who are most likely to benefit from gene therapy clinical trials and expedite the development of new therapies.”