Dataset Information

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease.

ABSTRACT: Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

SUBMITTER: Ong T

PROVIDER: S-EPMC6534121 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease.

Ong Tuyen T Pennesi Mark E ME Birch David G DG Lam Byron L BL Tsang Stephen H SH

Pharmaceutical research 20190107 2

Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene lea ...[more]

PMID: 30617669

Similar Datasets

Project description:BackgroundThis research aimed to establish recommendations on the clinical and genetic characteristics necessary to confirm patient eligibility for gene supplementation with voretigene neparvovec.MethodsAn expert steering committee comprising an interdisciplinary panel of Italian experts in the three fields of medical specialisation involved in the management of RPE65-associated inherited retinal disease (IRD) (medical retina, genetics, vitreoretinal surgery) proposed clinical questions necessary to determine the correct identification of patients with the disease, determine the fundamental clinical and genetics tests to reach the correct diagnosis and to evaluate the urgency to treat patients eligible to receive treatment with voretigene neparvovec. Supported by an extensive review of the literature, a series of statements were developed and refined to prepare precisely constructed questionnaires that were circulated among an external panel of experts comprising ophthalmologists (retina specialists, vitreoretinal surgeons) and geneticists with extensive experience in IRDs in Italy in a two-round Delphi process.ResultsThe categories addressed in the questionnaires included clinical manifestations of RPE65-related IRD, IRD screening and diagnosis, gene testing and genotyping, ocular gene therapy for IRDs, patient eligibility and prioritisation and surgical issues. Response rates by the survey participants were over 90% for the majority of items in both Delphi rounds. The steering committee developed the key consensus recommendations on each category that came from the two Delphi rounds into a simple and linear diagnostic algorithm designed to illustrate the patient pathway leading from the patient's referral centre to the retinal specialist centre.ConclusionsConsensus guidelines were developed to guide paediatricians and general ophthalmologists to arrive at the correct diagnosis of RPE65-associated IRD and make informed clinical decisions regarding eligibility for a gene therapy approach to RPE65-associated IRD. The guidelines aim to ensure the best outcome for the patient, based on expert opinion, the published literature, and practical experience in the field of IRDs.

Project description:Use of adeno-associated viral (AAV) vectors for liver-directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)-dependent autophagy in human hepatocytes. This cell response was critically required for efficient transduction because under conditions of impaired autophagy (pharmacological inhibition, small interfering RNA knockdown of autophagic proteins, or suppression by food intake), recombinant AAV-mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependence, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter, or AAV serotype and was subsequently confirmed in vivo. Specifically, short-term treatment with a single dose of torin 1 significantly increased vector-mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, coadministration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid-?-glucosidase in nonhuman primates.ConclusionWe identified autophagy as a pivotal cell response determining the efficiency of AAVs intracellular processing in hepatocytes and thus the outcome of liver-directed gene therapy using AAV vectors and showed in a proof-of-principle study how this virus-host interaction can be employed to enhance efficacy of this vector system. (Hepatology 2017;66:252-265).

Dataset Information

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease.

Publications

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets