Applied Genetic Technologies Corporation Inc. (Nasdaq: AGTC) has announced the publication of positive preclinical data for X-linked retinitis pigmentosa. The research study, entitled, “Dose Range Finding Studies With Two RPGR Transgenes in a Canine Model of X-linked Retinitis Pigmentosa Treated With Subretinal Gene Therapy” was published in the journal, Human Gene Therapy (2020 May 15. doi: 10.1089/hum.2019.337). The research was supported by AGCT Inc., and the University of Pennsylvania Perelman School of Medicine. The work was developed by a novel AAV treatment delivering a copy of the retinitis pigmentosa GTPase regulator (RPGR) gene. The results of the research are supported by the selection and use of the experimental treatment, termed by “AGTC-501”, previously dosed in clinical studies in patients with XLRP.
X-linked RP is one of the most common forms of retinitis pigmentosa and mutations in one gene, the RP GTPase regulator gene (RPGR gene), and is thought to account for approximately 75% of XLRP recorded cases. The gene encodes a ciliary protein that regulates trafficking of proteins to the outer segment of photoreceptors. Males are more severely affected by the X-linked pathology with night blindness generally occurring within the first decade of life, followed by restriction of the visual field and loss of visual acuity leading to legal blindness in most patients by the fourth to fifth decade of life.
In the preclinical study, a recombinant adeno-associated viral (rAAV) therapy has incorporated the GTPase regulator (RPGR) gene developing dose range-finding studies with an AAV2 capsid. Three surface tyrosine residues changed to phenylalanine (AAV2tYF) vector were administered by subretinal injection. According to the company, the full length RPGR protein contains repetitive sequences that can lead to instability during vector engineering and manufacturing. To overcoming this challenge a truncated RPGR protein is used to remove the repetitive sequence to stabilise the transcript. The publication reports data from dose-ranging studies of the vector utilizing AGTC’s proprietary rAAV2tYF capsid to deliver the RPGR DNA sequence in a canine model of XLRP. Commenting on the results to date, Sue Washer, President and CEO of AGTC stated that: “the results of these studies demonstrate our ability to integrate advances in vector and disease biology with expertise in DNA engineering to enable gene-based therapies that are safe, effective and amenable to our proprietary and industry-leading AAV manufacturing process. The data presented to date from our ongoing Phase 1/2 clinical program in XLRP using rAAV2tYF-GRK1-hRPGRco.