So far, CNGA3 mutations are not only one of the most common causes of achromatopsia and cone dystrophy or cone-rod dystrophy but also one of the most commonly mutated genes among various forms of retinopathy.
The purpose of this study was to examine the toxicity and side effects of a recombinant adeno-associated virus 8 (AAV8) vector, aimed to treat cyclic nucleotide gated channel alpha 3 (<i>CNGA3</i>)-linked achromatopsia, after a single subretinal administration in cynomolgus macaques.
This implicates ATF6 as having a major role in cone development and suggests that at least a subset of subjects with ATF6-ACHM have markedly fewer cellular targets for cone-directed gene therapies than do subjects with CNGA3- or CNGB3-ACHM.
Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATAp.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236delp.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD.
Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function.
Development of Methodology and Study Protocol: Safety and Efficacy of a Single Subretinal Injection of rAAV.hCNGA3 in Patients with CNGA3-Linked Achromatopsia Investigated in an Exploratory Dose-Escalation Trial.
The purpose of this study was to evaluate long-term efficacy and safety results of treatment, findings that hold great relevance for clinical trials that started recently in CNGA3achromatopsia patients.
Achromatopsia type 2 (ACHM2) is a severe, inherited eye disease caused by mutations in the <i>CNGA3</i> gene encoding the α subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel.
The cone mosaics in eyes with CNGA3 and CNGB3 variants are severely disrupted; the cone mosaics in patients with GNAT2-associated ACHM; however, have been reported to show a contiguous pattern in adaptive optics (AO) retinal images.
This novel mutation provides a large-animal model that is valid for most human CNGA3ACHM patients; the majority of them carry missense rather than premature-termination mutations.
Chromatic pupillography demonstrated significant reduced pupil responses to stimuli addressing primarily cone function, an increased sensitivity to rod-favoring stimuli and evidence for disinhibition of intrinsically photosensitive retinal ganglion cells in CNGA3-ACHM patients.
The cone mosaics in eyes with CNGA3 and CNGB3 variants are severely disrupted; the cone mosaics in patients with GNAT2-associated ACHM; however, have been reported to show a contiguous pattern in adaptive optics (AO) retinal images.
For example, a wild-type (WT) AAV5 vector can deliver a full-length Cnga3 (cyclic nucleotide-gated channel alpha-3) cDNA to target cells of the cone photoreceptor function loss 5 (cpfl5) mouse, a spontaneous animal model of achromatopsia with a Cnga3 mutation.
Here, we provide a detailed analysis of innate and adaptive immune response to clinical-grade AAV8 in non-human primates and compare this to preliminary clinical data from a retinal gene therapy trial for CNGA3-based achromatopsia (ClinicalTrials.gov: 02610582).
Here, we present a comprehensive spectrum of CNGB3 mutations and their prevalence in a cohort of 1074 independent families clinically diagnosed with achromatopsia.