Dataset Information

Gene-Based Therapeutics for Inherited Retinal Diseases.

ABSTRACT: Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber's congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.

SUBMITTER: Fenner BJ

PROVIDER: S-EPMC8782148 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Gene-Based Therapeutics for Inherited Retinal Diseases.

Fenner Beau J BJ Tan Tien-En TE Barathi Amutha Veluchamy AV Tun Sai Bo Bo SBB Yeo Sia Wey SW Tsai Andrew S H ASH Lee Shu Yen SY Cheung Chui Ming Gemmy CMG Chan Choi Mun CM Mehta Jodhbir S JS Teo Kelvin Y C KYC

Frontiers in genetics 20220107

Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber's congenital amaurosis due to <i>RPE65</i> mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this rev ...[more]

PMID: 35069693

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Project description:Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype-phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.

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:Inherited retinal diseases (IRDs) are a clinically and genetically diverse group of progressive degenerative disorders that can result in severe visual impairment or complete blindness. Despite their predominantly monogenic inheritance patterns, the genetic complexity of over 300 identified disease-causing genes presents a significant challenge in correlating clinical phenotypes with genotypes. Achieving a molecular diagnosis is crucial for providing patients with definitive diagnostic clarity and facilitating access to emerging gene-based therapies and ongoing clinical trials. Recent advances in next-generation sequencing technologies have markedly enhanced our ability to identify genes and genetic defects leading to IRDs, thereby propelling the development of gene-based therapies. The clinical success of voretigene neparvovec (Luxturna), the first approved retinal gene therapy for RPE65-associated Leber congenital amaurosis (LCA), has spurred considerable research and development in gene-based therapies, highlighting the importance of reviewing the current status of gene therapy for IRDs, particularly those utilizing adeno-associated virus (AAV)-based therapies. As novel disease-causing mutations continue to be discovered and more targeted gene therapies are developed, integrating these treatment opportunities into the standard care for IRD patients becomes increasingly critical. This review provides an update on the diverse phenotypic-genotypic landscape of IRDs, with a specific focus on recent advances in the understanding of IRDs in children with infantile nystagmus syndrome (INS). We highlight the complexities of the genotypic-phenotypic landscape of INS-associated IRDs, including conditions such as achromatopsia, LCA, congenital stationary night blindness, and subtypes of retinitis pigmentosa. Additionally, we provide an updated overview of AAV-based gene therapies for these diseases and discuss the potential of gene-based therapies for underlying IRDs that lead to INS, offering a valuable resource for pediatric patients potentially eligible for ongoing clinical trials.

Dataset Information

Gene-Based Therapeutics for Inherited Retinal Diseases.

Publications

Gene-Based Therapeutics for Inherited Retinal Diseases.

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