Project Details
Projekt
Development of novel gene therapy strategies for treatment of autosomal dominant retinitis pigmentosa in a pig model
Applicant
Professor Dr. Nikolai Klymiuk
Subject Area
Ophthalmology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 513025799
Retinitis pigmentosa (RP) is the most common inherited retinal disorder (IRD) affecting more than 2 million people worldwide. At present, promising therapies for IRDs aim at reconstituting gene function by expressing intact transcripts from recombinant adeno-associated virus (AAV) vectors. For autosomal dominant IRDs, however, such gene supplementation approaches are not applicable. Rather, they require the specific modification of the causative mutation or the unspecific disruption of both endogenous alleles to facilitate gene supplementation. Here, we aim at evaluating novel gene therapy approaches for a common form of autosomal dominant RP in a large animal model. A pig carrying a P347L mutation on of the pig RHO allels to test approaches at DNA- and/or RNA level. We will investigate (i) novel CRISPR-Cas9 and derivates, i.e. prime editors, to immediately correct the mutant allele; (ii) Cas13 derivates to efficiently knock-down of the disease-causing allele; (iii) a combination of CRISPR-Cas-mediated gene disruption and gene supplementation of RHO function. All approaches will be optimized in vitro and adapted for packaging into AAVs specifically shaped for transduction of photoreceptor cells. Finally, the therapeutic potential will be assessed in RHOP347L/+ pigs.
DFG Programme
Research Units
