Gene Therapy for Achromatopsia

Abstract

Achromatopsia is the most common cone dysfunction syndrome, affecting 1 in 30,000 people. It is an autosomal recessive disorder with a heterogeneous genetic background with variants reported in CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6. Up to 90% of achromatopsia patients harbour mutations in CNGA3 or CNB3, which encode for the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel in cone-specific phototransduction. The condition presents at birth or early infancy with poor visual acuity, nystagmus, photophobia, and colour vision loss in all axes. Multimodal retinal imaging has provided insightful information to characterise achromatopsia patients based on their genotype. There is no FDA-approved treatment for achromatopsia; however, studies have reported several preclinical gene therapies with anatomical and functional improvements reported in vivo. There are currently five gene therapy clinical trials registered for human patients at the phase I/II stage and for CNGA3 or CNGB3 causing achromatopsia. This review aims to discuss the genetics of achromatopsia, genotypic and phenotypic correlations in multimodal retinal imaging, and the developments and challenges in gene therapy clinical trials.

Keywords: achromatopsia; cone dysfunction; gene therapy.

Figure 1

Achromatopsia genes encoding proteins in the phototransduction cascade. Pictorial representation of the cone membrane with resultant intracellular hyperpolarization following light exposure and closure of the CNG channels. Five out of six genes associated with achromatopsia are depicted in pink and are involved in the phototransduction cascade steps indicated by arrows. CNGA3 and CNGB3, the most common achromatopsia genes, encode for two subunits of the cyclic nucleotide-gated channel in the plasma membrane. Meanwhile, GNAT2 encodes for cone transducin that acts to activate photodiesterase (PDE) to allow for hydrolysis of the second messenger cyclic guanosine monophosphate (cGMP). ATF6 is not represented in the figure, acting at the endoplasmic reticulum rather than at the plasma membrane. Figure produced using biorender.com (accessed on 15 April 2024).

Figure 2

Advancements in achromatopsia from vision restoration in animal models to clinical translation. Restoration of visual function in animal models (blue) over time until 2017 and clinical trials (green) currently registered in ClinicalTrials.gov in 2024 [50,51,52,53,54,55,56,57,58].

Figure 3

Considerations surrounding the administration of AAV gene therapy. Pictorial depiction of subretinal AAV with associated localised retinal detachment and administration of viral vector. The arrows show the process of cellular uptake of AAV, including uptake into nucleus with transcription and translation of gene of interest. Key concerns, including immunogenicity, potency and efficacy, genotoxicity, and persistence written in teal. Figure produced using biorender.com (accessed on 15 April 2024).