Retinal gene therapy for X-linked retinoschisis showed that AAV8 treatment had positive safety and tolerability outcomes

Researchers at the NIH, National Eye Institute, Bethesda have reported a phase I/IIa study on the use of an AAV8 vector for ocular gene delivery for the treatment of X-linked juvenile retinoschisis (XLRS).  While the small 9-patient study was focused on safety and tolerability, one participant in the trial provided the first signal of possible efficacy.  The positive data reported suggest that promising findings will be used to build “additional dose levels and strategies for immune suppression to control inflammatory sequela elicited by the vector”.  Nine participants were designed as a pilot safety trial, treated study eyes were neither masked nor randomized and only one eye was dosed per participant.


X-linked retinoschisis (XLRS) is a monogenic X-linked disease that leads to schisis (or splitting) of the neural retina leading to reduced visual acuity in approximately 12,000 males in the US.  The disorder affects visual acuity from an early age, typically with visual limitations in their daily function, including difficulty with reading, and obtaining a driver’s license.  According to the researchers, XLRS manifests haplosufficiency as female carriers have no evidence of the disease and demonstrate preservation of visual function and retinal structure across their lifespan.  As a consequence, using gene transfer as a therapeutic intervention may be capable to partially restore XLRS gene therapy.


The XLRS disease is caused by mutations in the RS1 gene coded by the retinoschisin protein secreted principally in the outer retina. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 (1X10^9) vector genomes (vg)/eye, 1e10 (1X10^10)  vg/eye, and 1e11 (1X10^11) vg/eye. According to the researchers, the investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Commenting in the paper, the research stated that the phase I/IIa dose-escalation trial of AAV8-RS1retinal gene transfer by intravitreal injection “is the first clinical study to explore treating a monogenic retinal degeneration by intravitreal application of an AAV8 vector serotype. The outcome measures focused on safety parameters and assessed the evidence of biologic activity”.