Translational Gene Therapy for CNGB1 Retinitis Pigmentosa

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Currently there is no treatment for autosomal recessive retinitis pigmentosa (arRP) due to mutations in rod photoreceptor genes. This multi-investigator, multi-center research project will fill this gap by optimizing recombinant adeno-associated virus (rAAV) vector gene augmentation therapy for cyclic nucleotide-gated channel beta 1 (CNGB1) linked RP. The optimized vector will be taken through the stages needed for an investigational new drug (IND) submission in preparation for a future phase I/II clinical trial. The collaborative team has expertise in rAAV vector development and production, preclinical and clinical trials for retinal dystrophies, clinical assessment and recruitment of arRP patients, CNG channel physiology and small and large animal proof-of-concept gene therapy studies. There are compelling reasons to select CNGB1-RP to fill this unmet need. First, CNGB1 mutations cause a loss of rod function, but only a slow loss of rods, meaning there is a wide window of opportunity for intervention while there are still remaining rods. Second, there are well characterized small (mouse) and large (dog) animal models of CNGB1-RP that recapitulate the human phenotype. Third, in both CNGB1-RP models rAAV gene augmentation therapy can efficiently (1) rescue the function and (2) delay the degeneration of rods. There are four aims to the project: Aim 1 is development of an optimized vector that efficiently and specifically targets rod photoreceptors in nonhuman primates. We will start with an efficient vector with a new short rhodopsin promoter that has already shown efficacy in CNGB1-RP animal models. The final rAAV-CNGB1 vector will be used to start the Good Manufacturing Practice (GMP) process development. This final vector will be used to investigate duration of rescue achievable in mouse and dog CNGB1-RP models and also answer the important question of "how late in the process of rod degeneration can rescue and preservation of structure be obtained?” Aim 2 will consist of recruitment of candidate patients for the clinical trial. A barrage of clinical testing methods will be used over a three year period to precisely describe the RP phenotype and identify optimal outcome measures for a future clinical trial. The testing will also ascertain if there is similar disease progression between the two eyes which would allow the second eye to be used as a non treatment control. Aim 3 will consist of the animal toxicology and pharmacokinetic and efficacy studies needed for IND submission. We propose a standard GLP toxicology/biodistribution study in rats coupled with a hybrid efficacy/safety study using the CNGB1-RP dog model. A pre-IND meeting with the FDA will review the study design and ensure that it meets regulatory requirements. GMP vector production will then be completed. Finally, in Aim 4 we will prepare and submit an IND application. This project fulfills the FOA goal of “development of a therapeutic, which can then be tested in a clinical trial.”