Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery

Abstract

This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. 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 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. 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. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887).

Dual Supramolecular Nanoparticle Vectors Enable CRISPR/Cas9‐Mediated Knockin of Retinoschisin 1 Gene—A Potential Nonviral Therapeutic Solution for X‐Linked Juvenile Retinoschisis

“…[ 6 ] Recently, a small number of clinical trials [ 7 ] were initiated to evaluate the safety and efficacy of adeno‐associated virus (AAV)‐based gene therapy approaches, which introduce functional retinoschisin in retina to treat XLRS. To date, none of the AAV‐based RS1 gene therapy approaches [ 8 ] has reached a satisfactory clinical endpoint. Meanwhile, researchers have been exploring CRISPR/Cas9‐mediated knockin of RS1 gene to achieve a curative therapeutic solution for XLRS.…”

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

“…The AAV8.RS1 Phase I/II three-dose-escalation trial (NCT02317887) for X-linked retinoschisis administers a healthy copy of retinoschisin to target photoreceptors and showed a dose-related intraocular inflammation that resolved with topical and oral steroids. 66 Systemic antibodies against AAV8 also increased in a dose-related fashion, but no antibodies against RS1 were observed.…”

“…Cukras et al postulated that the retinal degeneration associated with the X-linked retinoschisis also compromises the structural integrity of the internal limiting membrane, facilitating retinal penetration following intravitreal administration of the viral vector. 66 Little is known about the structural integrity of the internal limiting membrane in glaucoma patients and how much of a barrier this will pose to viral transduction for future gene therapy trials.…”

Suprachoroidal Delivery of Viral and Nonviral Gene Therapy for Retinal Diseases

“…Intravitreal delivery may also facilitate in-office gene therapy with transgene encoding secreted therapeutic proteins, which do not rely on transduction of specific retinal cells. Historically, the clinical success of intravitreal gene therapy for the treatment of IRDs has been limited 15,16 due to the presence of the internal limiting membrane, which lines the inner retina, and can hinder the penetration of viral vectors to underlying retinal layers such as PR and RPE. In addition, intravitreal administration leads to the dilution of the therapeutic agent within the vitreous cavity.…”