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Emerging Gene Therapy Treatments for Inherited Retinal Diseases
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Emerging Gene Therapy Treatments for Inherited Retinal Diseases

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (10 July 2022) | Viewed by 4069

Special Issue Editor

Dr. Livia S Carvalho

E-Mail Website
Guest Editor
Lions Eye Institute, University of Western Australia, Nedlands, WA, Australia
Interests: retinal degeneration; photoreceptors; inherited retinal diseases; gene therapy; AAV; cell death mechanisms; cone photoreceptors

Special Issue Information

Dear Colleagues,

With over 270 genes known to be involved in inherited retinal diseases (IRDs), translation of treatment strategies into clinical applications has been historically difficult. However, in recent years, there has been significant advances in basic research findings, including the development of several disease models, as well as translational studies focusing on gene therapy approaches, culminating in an increasing number of ongoing gene therapy clinical trials for inherited retinal diseases. The recent approval of Luxtruna® for Leber congenital amaurosis type 2 (LCA2) has established a clinical grounding and the safety of AAV-based gene therapies. However, with the recent advances of several new technologies, such as gene editing, antisense oligonucleotides and non-viral vectors, we need to start thinking about what we want the retinal gene therapy field to look like moving forward. This Special Issue of the Journal of Personalized Medicine aims to highlight the current state of the field and highlight some of the latest advances and technologies that are currently being evaluated to treat vision loss in IRDs.

Dr. Livia S Carvalho
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gene therapy
  • inherited retinal diseases
  • photoreceptor loss
  • viral vectors
  • non-viral vectors
  • CRISPR
  • antisense oligonucleotides
  • AAV

Published Papers (1 paper)

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Research

21 pages, 16397 KiB  
Article
Human iPSC-Derived Retinal Organoids and Retinal Pigment Epithelium for Novel Intronic RPGR Variant Assessment for Therapy Suitability
by Fidelle Chahine Karam, To Ha Loi, Alan Ma, Benjamin M. Nash, John R. Grigg, Darshan Parekh, Lisa G. Riley, Elizabeth Farnsworth, Bruce Bennetts, Anai Gonzalez-Cordero and Robyn V. Jamieson
J. Pers. Med. 2022, 12(3), 502; https://doi.org/10.3390/jpm12030502 - 21 Mar 2022
Cited by 8 | Viewed by 3600
Abstract
The RPGR gene encodes Retinitis Pigmentosa GTPase Regulator, a known interactor with ciliary proteins, which is involved in maintaining healthy photoreceptor cells. Variants in RPGR are the main contributor to X-linked rod-cone dystrophy (RCD), and RPGR gene therapy approaches are in clinical trials. [...] Read more.
The RPGR gene encodes Retinitis Pigmentosa GTPase Regulator, a known interactor with ciliary proteins, which is involved in maintaining healthy photoreceptor cells. Variants in RPGR are the main contributor to X-linked rod-cone dystrophy (RCD), and RPGR gene therapy approaches are in clinical trials. Hence, elucidation of the pathogenicity of novel RPGR variants is important for a patient therapy opportunity. Here, we describe a novel intronic RPGR variant, c.1415 − 9A>G, in a patient with RCD, which was classified as a variant of uncertain significance according to current clinical diagnostic criteria. The variant lay several base pairs intronic to the canonical splice acceptor site, raising suspicion of an RPGR RNA splicing abnormality and consequent protein dysfunction. To investigate disease causation in an appropriate disease model, induced pluripotent stem cells were generated from patient fibroblasts and differentiated to retinal pigment epithelium (iPSC-RPE) and retinal organoids (iPSC-RO). Abnormal RNA splicing of RPGR was demonstrated in patient fibroblasts, iPSC-RPE and iPSC-ROs, leading to a predicted frameshift and premature stop codon. Decreased RPGR expression was demonstrated in these cell types, with a striking loss of RPGR localization at the ciliary transitional zone, critically in the photoreceptor cilium of the patient iPSC-ROs. Mislocalisation of rhodopsin staining was present in the patient’s iPSC-RO rod photoreceptor cells, along with an abnormality of L/M opsin staining affecting cone photoreceptor cells and increased photoreceptor apoptosis. Additionally, patient iPSC-ROs displayed an increase in F-actin expression that was consistent with an abnormal actin regulation phenotype. Collectively, these studies indicate that the splicing abnormality caused by the c.1415 − 9A>G variant has an impact on RPGR function. This work has enabled the reclassification of this variant to pathogenic, allowing the consideration of patients with this variant having access to gene therapy clinical trials. In addition, we have identified biomarkers of disease suitable for the interrogation of other RPGR variants of uncertain significance. Full article
(This article belongs to the Special Issue Emerging Gene Therapy Treatments for Inherited Retinal Diseases)
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