Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials

AbstractWithin the last decade, continuous advances in molecular biological techniques have made it possible to develop causative therapies for inherited retinal disorders (IRDs). Some of the most promising options are gene-specific approaches using adeno-associated virus-based vectors to express a healthy copy of the disease-causing gene in affected cells of a patient. This concept of gene supplementation therapy is already advocated for the treatment of retinal dystrophy in RPE65-linked Leberʼs congenital amaurosis (LCA) patients. While the concept of gene supplementation therapy can be applied to treat autosomal recessive and X-linked forms of IRD, it is not sufficient for autosomal dominant IRDs, where the pathogenic gene product needs to be removed. Therefore, for autosomal dominant IRDs, alternative approaches that utilize CRISPR/Cas9 or antisense oligonucleotides to edit or deplete the mutant allele or gene product are needed. In recent years, research retinal gene therapy has intensified and promising approaches for various forms of IRD are currently in preclinical and clinical development. This review article provides an overview of current clinical trials for the treatment of IRDs.

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An Update on Gene Therapy for Inherited Retinal Dystrophy: Experience in Leber Congenital Amaurosis Clinical Trials

International Journal of Molecular Sciences ◽

10.3390/ijms22094534 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4534

Author(s):

Wei Chiu ◽

Ting-Yi Lin ◽

Yun-Chia Chang ◽

Henkie Isahwan-Ahmad Mulyadi Lai ◽

Shen-Che Lin ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Dystrophy ◽

Clinical Manifestations ◽

Adeno Associated Virus ◽

Leber Congenital Amaurosis ◽

Gene Therapies

Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye’s accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic RPE65 mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.

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129. Gene Therapy with Self-Complementary Recombinant Adeno-Associated Virus in Models of Autosomal Dominant Retinitis Pigmentosa Caused by RHO Mutations

Molecular Therapy ◽

10.1016/s1525-0016(16)35142-5 ◽

2014 ◽

Vol 22 ◽

pp. S48

Keyword(s):

Gene Therapy ◽

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Adeno Associated Virus ◽

Autosomal Dominant Retinitis Pigmentosa

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Enhancement of Muscle Gene Delivery with Pseudotyped Adeno-Associated Virus Type 5 Correlates with Myoblast Differentiation

Journal of Virology ◽

10.1128/jvi.75.16.7662-7671.2001 ◽

2001 ◽

Vol 75 (16) ◽

pp. 7662-7671 ◽

Cited By ~ 71

Author(s):

Dongsheng Duan ◽

Ziying Yan ◽

Yongping Yue ◽

Wei Ding ◽

John F. Engelhardt

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Gene Delivery ◽

Muscle Cells ◽

Therapeutic Benefit ◽

Transduction Efficiency ◽

Great Promise ◽

Adeno Associated Virus ◽

Muscle Gene ◽

Duchenne's Muscular Dystrophy

ABSTRACT Adeno-associated virus (AAV)-based muscle gene therapy has achieved tremendous success in numerous animal models of human diseases. Recent clinical trials with this vector have also demonstrated great promise. However, to achieve therapeutic benefit in patients, large inocula of virus will likely be necessary to establish the required level of transgene expression. For these reasons, efforts aimed at increasing the efficacy of AAV-mediated gene delivery to muscle have the potential for improving the safety and therapeutic benefit in clinical trials. In the present study, we compared the efficiency of gene delivery to mouse muscle cells for recombinant AAV type 2 (rAAV-2) and rAAV-2cap5 (AAV-2 genomes pseudo-packaged into AAV-5 capsids). Despite similar levels of transduction by these two vectors in undifferentiated myoblasts, pseudotyped rAAV-2cap5 demonstrated dramatically enhanced transduction in differentiated myocytes in vitro (>500-fold) and in skeletal muscle in vivo (>200-fold) compared to rAAV-2. Serotype-specific differences in transduction efficiency did not directly correlate with viral binding to muscle cells but rather appeared to involve endocytic or intracellular barriers to infection. Furthermore, application of this pseudotyped virus in a mouse model of Duchenne's muscular dystrophy also demonstrated significantly improved transduction efficiency. These findings should have a significant impact on improving rAAV-mediated gene therapy in muscle.

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Perspectives of people with inherited retinal diseases on ocular gene therapy in Australia: protocol for a national survey

BMJ Open ◽

10.1136/bmjopen-2020-048361 ◽

2021 ◽

Vol 11 (6) ◽

pp. e048361

Author(s):

Heather G Mack ◽

Fred K Chen ◽

John Grigg ◽

Robyn Jamieson ◽

John De Roach ◽

...

Keyword(s):

Quality Of Life ◽

Gene Therapy ◽

Clinical Trials ◽

Support Groups ◽

Retinal Dystrophy ◽

Retinal Disease ◽

Related Quality ◽

Biallelic Mutations ◽

The University

IntroductionVoretigene neparvovec-rzyl (Luxturna) was approved by the Australian Therapeutic Goods Administration on 4 August 2020 for the treatment of biallelic mutations in the RPE65 gene, a rare cause of congenital and adult-onset retinal dystrophy (predominantly Leber congenital amaurosis). Previous studies have shown that individuals who might participate in gene therapy trials overestimate clinical effect and underestimate risks. However, little is known about the perspectives of patients who may be offered approved gene therapy treatment for ocular conditions (as distinct from participating in clinical trials of gene therapy). The main objective of this study is to develop a tool to assess knowledge, attitudes and perceptions of approved and future genetic therapies among potential recipients of ocular gene therapy. In addition, we aim to assess the quality of life, attitudes towards clinical trials and vision-related quality of life among this cohort.Methods and analysisA new ‘Attitudes to Gene Therapy for the Eye’ tool will be developed following consultation with people with inherited retinal disease (IRD) and content matter experts. Australians with IRD or their guardians will be asked to complete an internet-based survey comprising existing quality of life and visual function instruments and items for the newly proposed tool. We expect to recruit 500 survey participants from patient support groups, the practices of Australian ophthalmologists who are specialists in IRD and Australian ophthalmic research institutions. Launch is anticipated early 2021. Responses will be analysed using item response theory methodology.Ethics and disseminationThis study has received ethics approval from the University of Melbourne (#2057534). The results of the study will be published in a peer-reviewed journal and will be presented at relevant conferences. Organisations involved in recruitment, and the Patient Engagement Advisory committee will assist the research team with dissemination of the study outcomes.

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Alzheimer’s disease: An overview of the current treatments

Bionatura ◽

10.21931/rb/cs/2019.02.01.17 ◽

2019 ◽

Vol 02 (Bionatura Conference Serie) ◽

Author(s):

Carolina Serrano-Larrea ◽

David Clavijo-Calderón

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Therapy ◽

Clinical Trials ◽

Nerve Growth Factor ◽

Phase 1 ◽

Phase 2 ◽

Adeno Associated Virus ◽

The World ◽

Phase 2 Clinical Trials

Alzheimer’s disease (AD) affects millions of people around the world and although there are treatments that help control symptoms and slow down the progress of the disease, there is still no cure. Current treatments include three acetylcholine inhibitors, a glutamate inhibitor and a combination of the two. Due to the failure of hundreds of clinical trials with monotherapies, multitarget treatments are currently being investigated that consider both brain and peripheral factors. Gene therapy is one of the most promising therapies to treat and prevent the development of AD. Nowadays, there is no available medical treatment based on gene therapy to treat AD; however, there are treatments in phase 1 and phase 2 clinical trials with promising results. In this review, we will focus on the most important gene therapy treatments, CERE-110 (adeno-associated virus AAV2-Nerve Growth Factor), Intracerebral AAV gene delivery of APOE2 and gene therapy using PPARγ-coactivator-1α(PGC-1α)

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Ocular Gene Therapy with Adeno-associated Virus Vectors: Current Outlook for Patients and Researchers

Journal of Ophthalmic and Vision Research ◽

10.18502/jovr.v15i3.7457 ◽

2020 ◽

Author(s):

Geoffrey A. Casey ◽

Kimberly M. Papp ◽

Ian M. MacDonald

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Gene Editing ◽

Gene Replacement ◽

Adeno Associated Virus ◽

Virus Vectors ◽

Gene Therapies ◽

Ocular Disorders ◽

Adenoassociated Virus ◽

Underlying Mechanisms

In this “Perspective”, we discuss ocular gene therapy – the patient’s perspective, the various strategies of gene replacement and gene editing, the place of adenoassociated virus vectors, routes of delivery to the eye and the remaining question - “why does immunity continue to limit efficacy?” Through the coordinated efforts of patients, researchers, granting agencies and industry, and after many years of pre-clinical studies, biochemical, cellular, and animal models, we are seeing clinical trials emerge for many previously untreatable heritable ocular disorders. The pathway to therapies has been led by the successful treatment of the RPE65 form of Leber congenital amaurosis with LUXTURNATM. In some cases, immune reactions to the vectors continue to occur, limiting efficacy. The underlying mechanisms of inflammation require further study, and new vectors need to be designed that limit the triggers of immunity. Researchers studying ocular gene therapies and clinicians enrolling patients in clinical trials must recognize the current limitations of these therapies to properly manage expectations and avoid disappointment, but we believe that gene therapies are well on their way to successful, widespread utilization to treat heritable ocular disorders.

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Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms222312818 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12818

Author(s):

Juliette Varin ◽

Clément Morival ◽

Noémien Maillard ◽

Oumeya Adjali ◽

Therese Cronin

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Risk Mitigation ◽

Gene Mutations ◽

Innate Immune ◽

Exclusion Criteria ◽

Retinal Surface ◽

Adeno Associated Virus ◽

Retinal Tissue ◽

Ocular Disorders

Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high clinical vector stocks, and the relatively immune-privileged environment of the eye explain such success. However, adverse effects due to AAV-delivery, though rare in the retina have led to the interruption of clinical trials. Risk mitigation, as the key to safe and efficient GT, has become the focus of ‘bedside-back-to-bench’ studies. Herein, we overview the inflammatory adverse events described in retinal GT trials and analyze which components of the retinal immunological environment might be the most involved in these immune responses, with a focus on the innate immune system composed of microglial surveillance. We consider the factors that can influence inflammation in the retina after GT such as viral sensors in the retinal tissue and CpG content in promoters or transgene sequences. Finally, we consider options to reduce the immunological risk, including dose, modified capsids or exclusion criteria for clinical trials. A better understanding and mitigation of immune risk factors inducing host immunity in AAV-mediated retinal GT is the key to achieving safe and efficient GT.

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