Complete achromatopsia is an inherited retinal disorder characterized by severely reduced visual acuity, nystagmus, severe photophobia, a small central scotoma, eccentric fixation, and complete loss of color discrimination. In 50% of patients with achromatopsia the disease is caused by mutations in the cyclic nucleotide gated channel beta subunit (CNGB3) gene. Preliminary studies indicate that gene therapy using a recombinant adeno-associated virus serotype 5 (rAAV5) vector expressing a human CNGB3 gene can restore cone photoreceptor function in a dog model of achromatopsia caused by mutations in the CNGB3 gene. The objectives of the studies proposed in this application are to confirm and extend these findings using a rAAV5-CNGB3 vector produced using a commercially relevant manufacturing method. This will be accomplished by producing and purifying a rAAV5-hCNGB3 vector and evaluating the safety and efficacy of subretinal administration of a range of vector concentrations (1 x 1010, 1 x 1011, and 1 x 1012 vg/mL) of the rAAV5-CNGB3 vector in a dog model of achromatopsia caused by mutations in the CNGB3 gene. Results of these studies will be important for future advanced development of rAAV-CNGB3 gene therapy for evaluation in patients with CNGB3-related achromatopsia.
Public Health Relevance: Complete achromatopsia is an inherited retinal disease characterized by severely reduced visual acuity and complete loss of color discrimination. In 50% of patients, the disease is caused by mutations in the CNGB3 gene. No treatment for achromatopsia is currently available. This project will evaluate a novel, CNGB3 gene therapy product for treatment of achromatopsia in a dog model.
Thesaurus Terms: Aav Vector; Advanced Development; Cng Channel (Rod); Canine Species; Canis Familiaris; Central Scotomas; Cognitive Discrimination; Color; Cone; Cones (Eye); Cones (Retina); Discrimination; Discrimination (Psychology); Disease; Disorder; Dogs; Fixation; Future; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genetic Alteration; Genetic Change; Genetic Intervention; Genetic Defect; Hereditary; Human; Human, General; Inherited; Intervention, Genetic; Light Sensitivity; Mammals, Dogs; Man (Taxonomy); Man, Modern; Methods; Modeling; Molecular Biology, Gene Therapy; Mutation; Nystagmus, Pathologic; Pathologic Nystagmus; Patients; Photophobia; Photoreceptors, Cone; Recombinant Adeno-Associated Virus; Recombinant Adeno-Associated Virus (Raav); Research Proposals; Retinal Cone; Retinal Diseases; Retinal Disorder; Safety; Serotyping; Therapy Evaluation; Therapy, Dna; Visual Acuity; Achromatopsia; Adeno-Associated Viral Vector; Adeno-Associated Virus Vector; Canine; Cationic Channel Protein (Rod); Cone Cell; Cyclic-Nucleotide Gated Channel; Cyclic-Nucleotide Gated Ion Channels; Disease/Disorder; Domestic Dog; Gene Therapy; Genetic Therapy; Genome Mutation; Novel; Nystagmus; Public Health Relevance; Retina Disease; Retina Disorder; Retinopathy; Sample Fixation; Vector
