An NCI Technology Opportunity Webinar
We invite you to register and join us on November 15 from 11:00 am – 12:00 pm ET for a free NCI technology webinar.
Attendees will hear from Drs. Anand Swaroop, Ph.D. and Kamil Kruczek, Ph.D. of the National Eye Institute about a new gene therapy method for treating CRX-autosomal dominant Leber Congenital Amaurosis (LCA). LCA is a rare genetic disease that is responsible for about 20% of all childhood blindness. It’s caused by mutations in any of at least 25 genes that control photoreceptor development or function. LCA has both recessive and dominant forms. Currently, there is an FDA approved gene therapy for treating only one of the recessive forms of LCA caused by mutations in the RPE65 gene. In addition to most recessive forms, the dominant form of LCA with underlying mutations in CRX remains untreatable.
Dr. Swaroop and his team developed a NEW gene therapy treatment for a dominant form of LCA that counteracts dominant mutations in the CRX gene. More specifically, correct CRX gene sequence packaged in an AAV vector was tested in retinal organoids derived from affected patients, resulting in partial recovery of proper photoreceptor development. Importantly, even partial recovery of photoreceptors should help patients regain useful vision. This new technology shows promise as a viable treatment for a currently untreatable rare disease condition.
Mutations in the cone rod homeobox (CRX) transcription factor can result in distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Adeno-Associated virus (AAV) vector-mediated delivery of a CRX cDNA under the control of a CRX promoter region partially restored photoreceptor phenotype and expression of phototransduction genes in an in vitro human retina model of CRX-LCA. Gene therapy using the CRX-AAV vector to retinal organoids derived from induced pluripotent stem cells (iPSCs) of a patient with the dominant CRX-I138fs mutation partially restored expression of visual opsins and other phototransduction genes as revealed by immunohistochemistry and single cell RNA-sequencing. Retinal organoids from iPSCs of a second dominant CRX-LCA patient carrying a K88N mutation also revealed loss of expression of opsins and phototransduction genes as a common phenotype, which could be alleviated by AAV-mediated overexpression of the CRX gene.