A group of researchers from Harvard Medical School and the University of Basel tested a gene therapy on mice with mutations in the PCDH15 gene, which causes USH1F. To date, the most effective way to deliver gene therapy to the retina is via an Adeno-associated Virus (AAV) vector. This approach is FDA-approved for the drug, Luxturna, the gene therapy available to patients with Leber congenital amaurosis. However, AAVs are limited in capacity and are unable to accommodate the large PCDH15 gene. To overcome this hurdle, researchers split the PCDH15 gene into two parts, packaging each part into an AAV, creating a dual-AAV gene therapy delivery system. They tested the efficacy of this gene therapy and delivery method on PCDH15 mouse models, human retinal organoids, and primate retinas. The PCDH15 gene was successfully delivered and subsequently expressed in the organoids and primate retinas, and the dual gene rescued visual function in the USH1F mice.
What this means for Usher syndrome: The ability to package and successfully deliver the large PCDH15 gene to the retina using this dual-AAV-vector approach opens the door for future development of gene therapies targeting other large genes that cause Usher syndrome like MYO7A (USH1B), CHD23 (USH1D), and USH2A.
