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

Cukras, Catherine ; Wiley, Henry E. ; Jeffrey, Brett G. ; Sen, H. Nida ; Turriff, Amy ; Zeng, Yong ; Vijayasarathy, Camasamudram ; Marangoni, Dario ; Ziccardi, Lucia and Kjellstrom, Sten LU , et al. (2018) In Molecular Therapy 26(9). p.2282-2294
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... (More)

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).

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publication status
published
subject
keywords
AAV vector, clinical trial, gene therapy, ocular disease, retinal disease, X-linked retinoschisis
in
Molecular Therapy
volume
26
issue
9
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85049454038
  • pmid:30196853
ISSN
1525-0016
DOI
10.1016/j.ymthe.2018.05.025https://doi.org/10.1016/j.ymthe.2018.05.025
language
English
LU publication?
yes
id
e758a7f3-b633-4ce9-b06d-e7d51beb0578
date added to LUP
2018-07-26 13:01:17
date last changed
2020-02-23 07:40:54
@article{e758a7f3-b633-4ce9-b06d-e7d51beb0578,
  abstract     = {<p>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).</p>},
  author       = {Cukras, Catherine and Wiley, Henry E. and Jeffrey, Brett G. and Sen, H. Nida and Turriff, Amy and Zeng, Yong and Vijayasarathy, Camasamudram and Marangoni, Dario and Ziccardi, Lucia and Kjellstrom, Sten and Park, Tae Kwon and Hiriyanna, Suja and Wright, J. Fraser and Colosi, Peter and Wu, Zhijian and Bush, Ronald A. and Wei, Lisa L. and Sieving, Paul A.},
  issn         = {1525-0016},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {2282--2294},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis : Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery},
  url          = {http://dx.doi.org/10.1016/j.ymthe.2018.05.025https://doi.org/10.1016/j.ymthe.2018.05.025},
  doi          = {10.1016/j.ymthe.2018.05.025https://doi.org/10.1016/j.ymthe.2018.05.025},
  volume       = {26},
  year         = {2018},
}