Applied Genetic (AGTC) Reports Early Data on Cone-Specific Promoters for Use in Gene Therapy of...
Thursday, January 7, 2016
Applied Genetic (AGTC) Reports Early Data on Cone-Specific Promoters for Use in Gene Therapy of Achromatopsia, Other Retinal Diseases
January 7, 2016 7:06 AM EST
Applied Genetic Technologies Corporation (Nasdaq: AGTC), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)-based gene therapies for the treatment of rare eye diseases, today announced preclinical data evaluating cone-specific promoters for use in gene therapy of achromatopsia (ACHM) and other retinal diseases. Results were published online in the peer-reviewed journal Human Gene Therapy and will appear in the January print issue.
In the study, AGTC investigators designed and constructed a series of short promoter sequences (PR1.1, PR1.5, and PR1.7) based on the 2.1 kb human L-opsin promoter (previously shown to efficiently and selectively drive gene expression in cone cells of mice and dogs). The novel short promoters were first evaluated for their efficiency and specificity in driving green fluorescent protein (GFP) expression in normal mice and cynomolgus macaques. The promoters were then tested for their ability to rescue cone function in a mouse disease model of achromatopsia associated with mutations in the CNGB3 gene. Mutations in CNGB3 are the underlying genetic cause of approximately half of achromatopsia cases in humans.
When tested in mice, each of the newly designed promoters directed high expression of GFP within photoreceptors. Based on these encouraging results, a subset of the promoters was selected for study in nonhuman primates. In this study, subretinal injection of an AAV-GFP vector containing the PR1.7 promoter led to strong and specific GFP expression in all cone photoreceptor types (including L-, M-, and S- cones, corresponding to red, green, and blue cones in humans). When tested in a CNGB3 mouse mutant model of achromatopsia, subretinal injection of an AAV-CNGB3 vector containing the PR1.7 promoter rescued cone function.
“These critical data informed the design of the CNGB3 expression cassette that AGTC is using in our human achromatopsia clinical study,” noted Sue Washer, President and CEO of AGTC.
This multiple-site clinical study will assess AGTC’s novel recombinant AAV vector expressing CNGB3 (rAAV2tYF-PR1.7-hCNGB3) in patients with congenital ACHM caused by mutations in the CNGB3 gene. The primary and secondary endpoints of the study will be safety and efficacy, respectively.
“These new preclinical data reinforce previous findings suggesting that novel AAV-based gene therapies may be effective in treating rare inherited retinal diseases. We look forward to advancing our clinical program and hope the resulting data will form the basis for a safe and effective therapy for ACHM-B3 achromatopsia,” Ms. Washer added.
AGTC is developing products for achromatopsia resulting from mutations in both the CNGB3 and CNGA3 genes, which together account for approximately 75 percent of the total achromatopsia patient population. The Company previously received orphan drug designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for its investigational gene therapy product for the treatment of achromatopsia caused by mutations in the CNGA3 gene.
Recent studies conducted by several of AGTC research partners including University of Florida, Hadassah-Hebrew University Medical Center, The Volcani Center and the Hebrew University of Jerusalem showed that in sheep affected by achromatopsia caused by mutations in the CNGA3 gene, delivery of an AAV vector carrying a healthy copy of the CNGA3 gene was able to restore cone photoreceptor function and the ability to navigate an obstacle maze course.