Achromatopsia: Genetics and Gene Therapy

Abstract

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.

Fig. 1

Known achromatopsia (ACHM) genes and their functions. A Most genes associated with ACHM encode proteins involved in phototransduction. The most common ACHM genes are CNGA3 and CNGB3, which encode the two subunits of the cyclic nucleotide-gated (CNG) channel, which is located in the plasma membrane of the outer segment. A less common disease gene is GNAT2, which encodes the cone transducin (G_t) that activates the phosphodiesterase (PDE6), which mediates the hydrolysis of the second messenger cyclic guanosine monophosphate (cGMP). The two genes encoding the cone PDE6 (PDE6C and PDE6H) have also been linked to ACHM. B The only known ACHM gene that does not encode a phototransduction cascade protein is ATF6. ATF6 is localized in the endoplasmic reticulum and is involved in endoplasmic reticulum stress and the unfolded protein response. The relative frequencies of ACHM mutations in Europe and Northern America are given next to the boxes with the gene names. Created with BioRender.com. GTP guanosine-triphosphate; retGC receptor guanylyl cyclase