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

Catherine Cukras, Henry E. Wiley, Brett G. Jeffrey, H. Nida Sen, Amy Turriff, Yong Zeng, Camasamudram Vijayasarathy, Dario Marangoni, Lucia Ziccardi, Sten Kjellstrom, Tae Kwon Park, Suja Hiriyanna, J. Fraser Wright, Peter Colosi, Zhijian Wu, Ronald A. Bush, Lisa L. Wei, Paul A. Sieving

Research output: Contribution to journalArticlepeer-review


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 ( NCT02317887).

Original languageEnglish
Pages (from-to)2282-2294
Number of pages13
JournalMolecular Therapy
Issue number9
Publication statusPublished - Sep 5 2018


  • AAV vector
  • clinical trial
  • gene therapy
  • ocular disease
  • retinal disease
  • X-linked retinoschisis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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