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

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.

scholarly journals Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

2021 ◽  
pp. bjophthalmol-2020-318483
Author(s):  
Malena Daich Varela ◽  
Thales Antonio Cabral de Guimaraes ◽  
Michalis Georgiou ◽  
Michel Michaelides
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Early Onset ◽  
Viral Vectors ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Dystrophy ◽  
European Medicines Agency ◽  
Current Management ◽  
Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.

Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials

2021 ◽  
Vol 238 (03) ◽  
pp. 272-281
Author(s):  
Stylianos Michalakis ◽  
Maximilian Gerhardt ◽  
Günter Rudolph ◽  
Siegfried Priglinger ◽  
Claudia Priglinger
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Product ◽  
Autosomal Dominant ◽  
Retinal Dystrophy ◽  
Adeno Associated Virus ◽  
Retinal Disorders ◽  
Alternative Approaches ◽  
Or Gene ◽  
Inherited Retinal Disorders

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.

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

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.

scholarly journals A review of recent developments in retinitis pigmentosa genetics, its clinical features, and natural course

2021 ◽  
Vol 9 (4) ◽  
Author(s):  
Eleftherios Loukovitis ◽  
Stoimeni Anastasia ◽  
Paris Tranos ◽  
Miltos Balidis ◽  
Solon Asteriadis ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Clinical Features ◽  
English Language ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Usher Syndrome ◽  
Retinal Dystrophy ◽  
Clinical Manifestations ◽  
Natural Course ◽  
Recent Developments

Background: Retinitis pigmentosa (RP), an inherited degenerative ocular disease, is considered the most common type of retinal dystrophy. Abnormalities of the photoreceptors, particularly the rods, and of the retinal pigment epithelium, characterizes this disease. The abnormalities progress from the midperiphery to the central retina. We here reviewed the developments in RP genetics in the last decade, along with its clinical features and natural course. Methods: The present review focused on articles in English language published between January 2008 and February 2020, and deposited in PubMed and Google Scholar databases. We searched for articles reporting on the clinical manifestations and genes related to both syndromic and non-syndromic RP. We screened and analyzed 139 articles, published in the last decade, referring to RP pathogenesis and identified, summarized, and highlighted the most significant genes implicated in either syndromic or non-syndromic RP pathogenesis, causing different clinical manifestations. Results: Recent literature revealed that approximately 80 genes are implicated in non-syndromic RP, and 30 genes in syndromic forms, such as Usher syndrome and Bardet‒Biedl syndrome (BBS). Moreover, it is estimated that 27 genes are implicated in autosomal dominant RP (adRP), 55 genes in autosomal recessive RP (arRP), and 6 genes in X-linked RP (xlRP), causing different RP phenotypes. Characteristically, RHO is the most prevalent adRP- and arRP-causing gene, and RPGR the most common xlRP-causing gene. Other important genes are PRPH2, RP1, CRX, RPE65, ABCA4, CRB1, and USH2Α. However, different phenotypes can also be caused by mutations in the same gene. Conclusions: The genetic heterogeneity of RP necessitates further study to map the exact mutations that cause more severe forms of RP, and to develop and use appropriate genetic or other effective therapies in future.

Chronic untreated retinal detachment in a patient with choroideremia provides insight into the disease process and potential therapy

2021 ◽  
pp. 112067212199472
Author(s):  
Maria Pilar Martin-Gutierrez ◽  
Thomas MW Buckley ◽  
Robert E MacLaren
Keyword(s):  
Gene Therapy ◽  
Retinal Detachment ◽  
Rhegmatogenous Retinal Detachment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Dystrophy ◽  
Disease Process ◽  
Peripheral Retina ◽  
Inherited Retinal Dystrophy ◽  
Insight Into

Aim: We present the case of a 72-year-old male with advanced choroideremia and a left chronic rhegmatogenous retinal detachment, which to our knowledge is the first formal report of a retinal detachment in this disease. Background: Choroideremia is a rare X-linked inherited retinal dystrophy, caused by mutations in the CHM gene which encodes Rab escort protein 1 (REP1), and affected males typically experience a progressive centripetal loss of vision. The disease pathology is caused by a primary retinal pigment epithelium degeneration, which leads to secondary loss of photoreceptors and choriocapillaris. This in turn leads to fusion of the degenerate outer retinal layers resulting in a retinopexy that is known to make subretinal gene therapy particularly challenging in these patients. Conclusion: Although retinal gene therapy is commonly targeted to the macular area in choroideremia, the observation of a rhegmatogenous retinal detachment indicates that the peripheral retina may not fuse with the residual choroid as occurs in the equatorial and macular regions. If this hypothesis is correct, targeting gene therapy to the retinal periphery even in advanced cases may be feasible and could potentially be used to preserve navigational vision.

scholarly journals BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure

2018 ◽  
Vol 115 (12) ◽  
pp. E2839-E2848 ◽  
Author(s):  
Karina E. Guziewicz ◽  
Artur V. Cideciyan ◽  
William A. Beltran ◽  
András M. Komáromy ◽  
Valerie L. Dufour ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Light Exposure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Disease Model ◽  
Moderate Intensity ◽  
Adeno Associated Virus ◽  
Sensitivity Loss ◽  
Therapy Success

Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE–PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE–PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE–PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.

scholarly journals Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector

2018 ◽  
Vol 115 (36) ◽  
pp. E8547-E8556 ◽  
Author(s):  
Artur V. Cideciyan ◽  
Raghavi Sudharsan ◽  
Valérie L. Dufour ◽  
Michael T. Massengill ◽  
Simone Iwabe ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Imaging ◽  
Large Animal Model ◽  
Large Animal ◽  
Complete Suppression ◽  
Aav Vector ◽  
Retinal Degenerations

Inherited retinal degenerations are caused by mutations in >250 genes that affect photoreceptor cells or the retinal pigment epithelium and result in vision loss. For autosomal recessive and X-linked retinal degenerations, significant progress has been achieved in the field of gene therapy as evidenced by the growing number of clinical trials and the recent commercialization of the first gene therapy for a form of congenital blindness. However, despite significant efforts to develop a treatment for the most common form of autosomal dominant retinitis pigmentosa (adRP) caused by >150 mutations in the rhodopsin (RHO) gene, translation to the clinic has stalled. Here, we identified a highly efficient shRNA that targets human (and canine)RHOin a mutation-independent manner. In a single adeno-associated viral (AAV) vector we combined this shRNA with a humanRHOreplacement cDNA made resistant to RNA interference and tested this construct in a naturally occurring canine model ofRHO-adRP. Subretinal vector injections led to nearly complete suppression of endogenous canineRHORNA, while the humanRHOreplacement cDNA resulted in up to 30% of normal RHO protein levels. Noninvasive retinal imaging showed photoreceptors in treated areas were completely protected from retinal degeneration. Histopathology confirmed retention of normal photoreceptor structure and RHO expression in rod outer segments. Long-term (>8 mo) follow-up by retinal imaging and electroretinography indicated stable structural and functional preservation. The efficacy of this gene therapy in a clinically relevant large-animal model paves the way for treating patients withRHO-adRP.

Major Hereditary Gastrointestinal Cancer Syndromes: a Narrative Review

2017 ◽  
Vol 26 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Lakshmi Manogna Chintalacheruvu ◽  
Trudy Shaw ◽  
Avanija Buddam ◽  
Osama Diab ◽  
Thamer Kassim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Genetic Testing ◽  
Gastrointestinal Cancer ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Clinical Manifestations ◽  
Micro Rna ◽  
Diffuse Gastric Cancer ◽  
Adenomatous Polyposis ◽  
Cancer Syndromes

Gastrointestinal cancer is one of the major causes of death worldwide. Hereditary gastrointestinal cancer syndromes constitute about 5-10% of all cancers. About 20-25% of undiagnosed cases have a possible hereditary component, which is not yet established. In the last few decades, the advance in genomics has led to the discovery of multiple cancer predisposition genes in gastrointestinal cancer. Physicians should be aware of these syndromes to identify high-risk patients and offer genetic testing to prevent cancer death. In this review, we describe clinical manifestations, genetic testing and its challenges, diagnosis and management of the major hereditary gastrointestinal cancer syndromes.Key words:  −  −  −  − .Abbreviations: ACG: American College of Gastroenterology; AFAP: attenuated FAP; APC: adenomatous polyposis coli; CDH1: E-cadherin; CHRPE: congenital hypertrophy of the retinal pigment epithelium; CRC: colorectal cancer; FAMMM: Familial atypical multiple mole melanoma; FAP: Familial adenomatous polyposis; GC: gastric cancer; HDGC: Hereditary diffuse gastric cancer; IHC: immunohistochemical; IPAA: ileal pouch–anal anastomosis; IRA: ileorectal anastomosis; MSI: microsatellite instability; MMR: mismatch repair; miRNA: micro RNA.

scholarly journals Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

2021 ◽  
Vol 6 (1) ◽  
pp. e000774
Author(s):  
Minwei Wang ◽  
Shiqi Su ◽  
Shaoyun Jiang ◽  
Xinghuai Sun ◽  
Jiantao Wang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Amyloid Β Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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