2018
DOI: 10.1016/j.ymthe.2018.05.025
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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, prospectiv… Show more

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Cited by 193 publications
(169 citation statements)
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“…[ 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.…”
Section: Methodsmentioning
confidence: 99%
“…[ 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.…”
Section: Methodsmentioning
confidence: 99%
“…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.…”
Section: Gene Therapymentioning
confidence: 96%
“…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.…”
Section: Gene Therapymentioning
confidence: 99%
“…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.…”
Section: Intravitreal Administrationmentioning
confidence: 99%