A single mutation-independent AAV gene therapy for the treatment of autosomal-dominant retinitis pigmentosa.

PROJECT SUMMARY Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) affecting 1 in every 4,000 people in the US. It is a blinding eye disorder characterized by progressive bilateral degeneration of rod photoreceptors that initially causes night blindness, followed by a gradual loss of peripheral rods. Although dysmorphic cone somas persist, a full field light stimulus does not evoke an electroretinogram (ERG) response. Currently there is no FDA ap- proved treatment for any form of autosomal-dominant retinitis pigmentosa (adRP) and there is an urgent unmet medical need to develop effective therapies. Dominant RHO mutations are typically gain-of-function and treat- ment approaches require elimination (knockdown) of the mutant rhodopsin. adRP resulting from mutations in rhodopsin are the most common IRD (25-40% of all adRP cases). By comparison, a single RHO mutation, Pro23His (P23H) RHO mutation is found in ~1/3 of adRP patients, or 8.5% of all RP. With >150 RHO mutations identified so far, taking a mutation-specific approach is not commercially feasible. Since targeting mutant rhodopsin in a mutation-independent strategy is technically challenging, both mutant and WT alleles are usually knocked down, along with replacement therapy for the WT allele. To meet this chal- lenge, Opus Genetics is developing OPGx-RHO, an AAV5-based single vector containing two key elements to achieve knockdown of endogenous RHO (mutant and WT) and a codon optimized human RHO cDNA that re- places WT RHO and is resistant to degradation by the knockdown element, shRNA820. T4R Rho-mutant dogs, a naturally occurring canine model of RHO-adRP is susceptible to acute light damage. When pretreated with OPGx-RHO via subretinal administration, OPGx-RHO efficiently preserved the integrity of the outer retina, as determined by measuring outer nuclear layer (ONL) thickness, as well as rod and cone morphology, within two weeks of light damage. The efficacy of OPGx-RHO with a single subretinal administration is durable, as it pro- tects T4R Rho-mutant dog retinas against repeated light exposures at 11-, 15-, 25-, and 35-weeks post-injection. A safety/toxicology study in T4R Rho-mutant dogs demonstrated that OPGx-RHO is well tolerated. As a single vector containing the key elements for knockdown-and-replacement, OPGx-RHO offers an innovative approach for the treatment of any adRP resulting from a mutation in rhodopsin. This Direct to Phase II application will fulfill FDA recommendations from our pre-IND meeting and complete chemistry, manufacturing and controls of a clin- ical-grade batch of OPGx-RHO, including clinical device compatibility and extended stability studies (aim 1). We also will carry out efficacy and safety/toxicology studies in a second large animal model, transgenic pigs ex- pressing the complete human P23H RHO protein (TgP23H pigs) (aim 2). TgP23H pigs have proven a valuable animal model characterized by an inheritance pattern and retinal dysfunction that mimics human adRP. Pigs offer other advantages compared to other animal models, including a large eye that is similar in size and vitreal volume as the human eye, and share a similar spatial distribution of rod and cone photoreceptors.