Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR

Abstract

Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people 1 , 2 , 3 , 4 , 5 , 6 . Here we report the first in human Phase I/II dose escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene 7 in 18 patients up to 6 months follow-up ( Clinicaltrials.gov : NCT03116113). The primary outcome of the study was safety and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no significant safety concerns following subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8. coRPGR ) 8 meeting the pre-specified primary endpoint. Visual field improvements beginning at one month and maintained to the last point of follow-up were observed in six patients.

Genome-Editing Strategies for Treating Human Retinal Degenerations

“…The proven safety and clinical success of AAV vector-mediated gene supplementation in treating recessive IRDs associated with loss-of-function mutations 3,6,7 suggests that new gene editing strategies would be best applied to mutations unamenable to this approach.…”

“…Adeno-associated viral (AAV) vectors are the most frequently used vehicles for delivering genetic material into cells due to their high tropism for outer retinal cells and good safety profile 5 . In addition to Luxturna, AAV-mediated gene supplementation therapies to deliver working copies of disease-associated genes into retinal cells in recessive retinal degenerations, for instance, choroideremia and RPGR-associated X-linked retinitis pigmentosa, are being evaluated in advanced stage clinical trials with promising safety and efficacy data 6,7 . However, due to a maximum total coding capacity of ~4.8 kb, many large disease-associated genes cannot be delivered using a single AAV vector, including ABCA4 (6.8 kb) in Stargardt disease and USH2A (15.6 kb) in Usher syndrome type 2 8 .…”

FDA Prioritizes Biomarin's Hemophilia Gene Therapy

“…''It is becoming more apparent to us that novel genetic therapies, when working, lead to a clear improvement in neuronal function, which holds great hope for a variety of other degenerative conditions that have a genetic basis.'' 5,6 Nightstar was established in 2014 as a spinoff of the University of Oxford, from which the company licenses the gene therapy.…”

Promoter Orientation within an AAV-CRISPR Vector Affects Cas9 Expression and Gene Editing Efficiency

“…1 AAV vectors have been used across a range of clinical gene therapy trials for efficient and safe transgene delivery. [2][3][4] The CRISPR-Cas9 system can be packaged in AAV and has been used to edit genes in the liver, [5][6][7][8] retina, 1,9-12 brain, 13 heart, 14,15 and skeletal muscle [16][17][18] in animal models.…”