Gene therapy for inherited retinal and optic nerve degenerations

Abstract

The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

Stargardt macular dystrophy and evolving therapies

“…Currently, Oxford Biomedica in coordination with Sanofi, is sponsoring an escalating dose Phase I/II clinical trial of SAR422459, formerly known as StarGen™ (NCT 01367444), investigating safety and preliminary signs of efficacy in STGD1 over a 48 week follow up period [66] [60]. The trial, which plans to enroll an estimated 46 patients, began in June 2011 and has an expected completion date in November 2019.…”

“…It is unclear if avacincaptad pegol, another C5 complement inhibitor, will be more successful in AMD/STGD1, but perhaps intravitreal injection delivery may allow for better retinal drug levels than intravenous infusion. Viral vector gene therapy has been approved for RPE65 mutation associated retinal dystrophy [60,73], which has spurred interest in gene therapy for STGD1, although the ABCA4 gene is too large for AAV vectors and will require an alternative approach. Similar excitement surrounds the potential of stem cell therapy to treat STGD1.…”

Gene therapy and the adeno‐associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations

“…RPGR is another commonly mutated gene in RP. RPGR is mutated in about 70% of X‐linked RP (XLRP) and affects mostly males, while heterozygous females display a wide variation in clinical symptoms. RPGR is localized to the cilium that connects the outer and inner photoreceptor segments and is thought to play a role in protein transport between these segments .…”

“…This is partially due to fact that retinoschisin is expressed throughout the retina, necessitating a therapy that can treat it in its entirety. Additionally, the retinas in XLRS patients are more fragile due to the disruption of the cellular structure and the propensity for developing fluid‐filled cysts that could be further exacerbated with vitrectomy, which is necessary prior to subretinal injection, or by improper positioning of the needle, leading to vector administration into an area of schisis …”

“…Additionally, the retinas in XLRS patients are more fragile due to the disruption of the cellular structure and the propensity for developing fluid-filled cysts that could be further exacerbated with vitrectomy, which is necessary prior to subretinal injection, or by improper positioning of the needle, leading to vector administration into an area of schisis. 47 The National Eye Institute is conducting a phase I-II trial (NCT02317887) evaluating the safety and tolerability of an intravitreal injection of an AAV8 vector encoding the RS1 gene (AAV8-scRS/IRBPhRS) in an attempt to induce the production of normal retinoschisin from retinal cells. Recruitment aims to treat 24 patients in three dose escalating interventional arms to evaluate the retinal function, ocular structure and adverse events at multiple time points over a 15-y period.…”