Review
Neurosciences
Samantha R. De Silva, Anthony T. Moore
Summary: Inherited retinal degenerations, such as retinitis pigmentosa, are a major cause of blindness in working age adults. Optogenetics, a method that uses light to activate retinal cells, shows potential for restoring visual function in patients with advanced retinal degeneration. Several clinical trials are currently underway to investigate this approach.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Review
Cell Biology
Lindsey A. Chew, Alessandro Iannaccone
Summary: Most patients with inherited retinal degenerations (IRDs) have been waiting for cures for decades, and alternative approaches are needed for genetically and phenotypically diverse IRD patients. This review highlights gene-agnostic approaches being developed as therapeutics for IRDs.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Letter
Genetics & Heredity
Kirk A. J. Stephenson, Julia Zhu, Niamh Wynne, Adrian Dockery, Rebecca M. Cairns, Emma Duignan, Laura Whelan, Conor P. Malone, Hilary Dempsey, Karen Collins, Shana Routledge, Rajiv Pandey, Elaine Crossan, Jacqueline Turner, James J. O'Byrne, Laura Brady, Giuliana Silvestri, Paul F. Kenna, G. Jane Farrar, David J. Keegan
Summary: Target 5000 is an efficient and effective service for diagnosing and managing inherited retinal degenerations, providing personalized care plans for patients through genetic sequencing and collaboration with multidisciplinary teams. This service not only offers diagnosis, but also discovers novel genes and variants implicated in IRD, serving as a model for the development of similar programs in other countries.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Ophthalmology
Malena Daich Varela, Giovanni Marco Conti, Samantha Malka, Veronika Vaclavik, Omar A. Mahroo, Andrew R. Webster, Viet Tran, Michel Michaelides
Summary: This study describes the largest, most phenotypically and genetically diverse cohort of patients with inherited retinal disease (IRD)-related Coats-like vasculopathy (CLV) to date. The prevalence of IRD-related CLV is rare, sporadic, mostly bilateral, and associated with a poor prognosis. It can occur in different types of IRD at any stage of the disease.
Review
Ophthalmology
Malena Daich Varela, Burak Esener, Shaima A. Hashem, Thales Antonio Cabral de Guimaraes, Michalis Georgiou, Michel Michaelides
Summary: Ophthalmic genetics has rapidly evolved in the past decade, particularly in translational medicine for inherited retinal diseases. This review discusses various methods for objectively and accurately assessing retinal structure in IRD patients, including standard imaging techniques and newer technologies, showing their utility in ongoing therapeutic efforts/trials.
BRITISH JOURNAL OF OPHTHALMOLOGY
(2021)
Review
Ophthalmology
Malena Daich Varela, Michalis Georgiou, Shaima A. Hashem, Richard G. Weleber, Michel Michaelides
Summary: Functional assessments play a crucial role in the clinical evaluation of patients with inherited retinal diseases, with a significant impact on various intervention approaches. These assessments help diagnose and monitor specific genotypes, but also come with limitations and challenges, requiring exploration of more effective analytical methods.
BRITISH JOURNAL OF OPHTHALMOLOGY
(2022)
Review
Genetics & Heredity
Chitra Kannabiran, Deepika Parameswarappa, Subhadra Jalali
Summary: This review discusses the genetic studies on retinitis pigmentosa in India and neighboring South Asian countries. These populations have been understudied in this aspect, but efforts have been made to identify the genetic characteristics of RP in Indian families and large extended families from Pakistan. The extreme clinical and genetic heterogeneity of RP poses challenges in identifying associated genes and translating research findings for better disease management.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Kirk A. J. Stephenson, Julia Zhu, Adrian Dockery, Laura Whelan, Tomas Burke, Jacqueline Turner, James J. O'Byrne, G. Jane Farrar, David J. Keegan
Summary: Inherited retinal degenerations (IRDs) are a common cause of blindness in the working age population. Genetic testing plays a crucial role in diagnosing IRDs, with first-tier panel-based next-generation sequencing having a high success rate. This study demonstrates the reassessment of patients with negative results from first-tier testing and the effectiveness of second-tier genetic testing methods. By utilizing appropriate genetic testing techniques, the overall resolution rate of previously unresolved cases was increased to 92%. First-tier testing remains the most cost-effective approach, and second-tier testing should be guided by clinical and genetic indications to achieve a genetic diagnosis in a cost-effective manner.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Clinical Neurology
Giulia Coarelli, Thomas Wirth, Christine Tranchant, Michel Koenig, Alexandra Durr, Mathieu Anheim
Summary: This narrative review provides an update on the management of inherited cerebellar ataxias (ICAs), including main clinical entities, genetic analysis strategies, and recent therapeutic developments. It offers support for diagnosis, genetic counseling, and therapeutic management of ICAs in clinical practice.
JOURNAL OF NEUROLOGY
(2023)
Article
Genetics & Heredity
Julia Zhu, Kirk A. J. Stephenson, Adrian Dockery, Jacqueline Turner, James J. O'Byrne, Susan Fitzsimon, G. Jane Farrar, D. Ian Flitcroft, David J. Keegan
Summary: Inherited retinal degenerations (IRDs) account for a significant proportion of pediatric blindness, and there are often long delays in reaching a diagnosis. In this study, a telegenetics approach was used to offer genetic testing to children with phenotypic evidence of IRD during the COVID-19 pandemic. Genetic testing identified causative genetic variants in a high percentage of patients, and a significant proportion were eligible for approved therapies or clinical trial-based gene therapies. Early introduction of genetic testing is crucial for genetic counseling and preparation for upcoming gene therapy trials in pediatric IRD patients.
Article
Medicine, Research & Experimental
Jinjie Ling, Laura A. Jenny, Ashley Zhou, Stephen H. Tsang
Summary: Since the development of CRISPR/Cas9 gene editing in 2012, therapeutic editing research has progressed through several phase 1-2a trials. This article provides an overview of the mechanisms and applications of various gene-editing technologies for the treatment of inherited retinal diseases (IRDs), including adeno-associated virus vectors, lentiviruses, CRISPR/Cas9 systems, base and prime editing, antisense oligonucleotides, short-hairpin RNAs, Cas13, and adenosine deaminase acting on RNA. The article also highlights the impact of these technologies on advancing the practice of medicine.
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE
(2023)
Article
Multidisciplinary Sciences
Mythily Ganapathi, Amanda Thomas-Wilson, Christie Buchovecky, Avinash Dharmadhikari, Subit Barua, Winston Lee, Merry Z. C. Ruan, Megan Soucy, Sara Ragi, Joy Tanaka, Lorraine N. Clark, Ali B. Naini, Jun Liao, Mahesh Mansukhani, Stephen Tsang, Vaidehi Jobanputra
Summary: This study aimed to evaluate the effectiveness of exome sequencing (ES) in the diagnosis of inherited retinal disorders. The results showed the clinical utility of ES in the diagnosis of genetically heterogeneous retinal disorders.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Tamar Ben Yosef, Eyal Banin, Elana Chervinsky, Stavit A. Shalev, Rina Leibu, Eedy Mezer, Ygal Rotenstreich, Nitza Goldenberg-Cohen, Shirel Weiss, Muhammad Imran Khan, Daan M. Panneman, Rebekkah J. Hitti-Malin, Chen Weiner, Susanne Roosing, Frans P. M. Cremers, Eran Pras, Dinah Zur, Hadas Newman, Iris Deitch, Dror Sharon, Miriam Ehrenberg
Summary: This study aims to describe the phenotype frequency and genetic basis of inherited retinal diseases (IRDs) among Israeli Jewish patients of Ethiopian ancestry. The most common phenotypes observed were Stargardt disease and nonsyndromic retinitis pigmentosa, with autosomal recessive inheritance being the most common mode of inheritance. The findings of this study can assist in clinical and molecular diagnosis and potentially contribute to the development of adequate therapy in the future.
Review
Health Care Sciences & Services
Oscar Onyango, Marianne Mureithi, Dennis Kithinji, Walter Jaoko, Kaoru Fujinami
Summary: Inherited retinal dystrophies (IRDs) are a global problem, with limited research conducted among indigenous black Africans. This literature review aims to identify challenges and opportunities for progress in IRD genetic research conducted among indigenous Africans. The review identified 11 articles, highlighting the use of next-generation sequencing, whole exome sequencing, and Sanger sequencing as the main genetic testing methods. The main IRDs characterized were retinitis pigmentosa, Leber Congenital Amaurosis, Stagardt disease, and cone dystrophy, with implicated genes including MERTK, GUCY2D, ABCA4, and KCNV2.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Multidisciplinary Sciences
Hamideh Sabbaghi, Sina Madani, Hamid Ahmadieh, Narsis Daftarian, Fatemeh Suri, Farid Khorrami, Proshat Saviz, Mohammad Hasan Shahriari, Tahmineh Motevasseli, Sahba Fekri, Ramin Nourinia, Siamak Moradian, Abbas Sheikhtaheri
Summary: The purpose of this study was to present a classification of inherited retinal diseases (IRDs) and compare its content coverage with common standard terminology systems. A panel of experts annotated a list of IRDs based on a comprehensive literature review and leveraged clinical terminologies from various reference sets. The classification system can be used for IRD clinical documentation and is a preliminary step toward developing a more robust standard ontology for IRDs or updating available standard terminologies. The content coverage of the proposed classification was highest for UMLS.
Article
Neurosciences
Arpad Palfi, Adlet Yesmambetov, Pete Humphries, Karsten Hokamp, G. Jane Farrar
FRONTIERS IN NEUROSCIENCE
(2020)
Article
Cell & Tissue Engineering
Amelia Lane, Katarina Jovanovic, Ciara Shortall, Daniele Ottaviani, Anna Brugulat Panes, Nele Schwarz, Rosellina Guarascio, Matthew J. Hayes, Arpad Palfi, Naomi Chadderton, G. Jane Farrar, Alison J. Hardcastle, Michael E. Cheetham
Article
Multidisciplinary Sciences
Sophia Millington-Ward, Naomi Chadderton, Megan Berkeley, Laura K. Finnegan, Killian S. Hanlon, Matthew Carrigan, Peter Humphries, Paul F. Kenna, Arpad Palfi, G. Jane Farrar
SCIENTIFIC REPORTS
(2020)
Article
Genetics & Heredity
Zeinab Fadaie, Laura Whelan, Adrian Dockery, Catherina H. Z. Li, L. Ingeborgh van der Born, Carel B. Hoyng, Christian Gilissen, Jordi Corominas, Charlie Rowlands, Roly Megaw, Anne K. Lampe, Frans P. M. Cremers, Gwyneth Jane Farrar, Jamie M. Ellingford, Paul F. Kenna, Susanne Roosing
Summary: Through whole genome sequencing and functional analysis, a branchpoint variant in BBS1 was identified, resulting in non-syndromic RP in four unrelated individuals. This study highlights the importance of analyzing non-coding regions to provide a conclusive molecular diagnosis.
JOURNAL OF MEDICAL GENETICS
(2022)
Letter
Genetics & Heredity
Kirk A. J. Stephenson, Julia Zhu, Niamh Wynne, Adrian Dockery, Rebecca M. Cairns, Emma Duignan, Laura Whelan, Conor P. Malone, Hilary Dempsey, Karen Collins, Shana Routledge, Rajiv Pandey, Elaine Crossan, Jacqueline Turner, James J. O'Byrne, Laura Brady, Giuliana Silvestri, Paul F. Kenna, G. Jane Farrar, David J. Keegan
Summary: Target 5000 is an efficient and effective service for diagnosing and managing inherited retinal degenerations, providing personalized care plans for patients through genetic sequencing and collaboration with multidisciplinary teams. This service not only offers diagnosis, but also discovers novel genes and variants implicated in IRD, serving as a model for the development of similar programs in other countries.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Biochemistry & Molecular Biology
Janine Reurink, Adrian Dockery, Dominika Ozieblo, G. Jane Farrar, Monika Oldak, Jacoline B. ten Brink, Arthur A. Bergen, Tuula Rinne, Helger G. Yntema, Ronald J. E. Pennings, L. Ingeborgh van den Born, Marco Aben, Jaap Oostrik, Hanka Venselaar, Astrid S. Plomp, M. Imran Khan, Erwin van Wijk, Frans P. M. Cremers, Susanne Roosing, Hannie Kremer
Summary: This study assessed unscreened or incompletely screened USH2 and arRP cases for likely pathogenic USH2A variants using MIP-based sequencing, successfully identifying (likely) pathogenic variants in a majority of cases. The effectiveness of MIP-based sequencing as a screening tool for USH2A was confirmed, with seven unexplained cases selected for future analysis with whole genome sequencing.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Adrian Dockery, Laura Whelan, Pete Humphries, G. Jane Farrar
Summary: Inherited retinal diseases (IRDs) encompass a variety of genetically diverse conditions with phenotypic variations, researchers utilize cutting-edge sequencing techniques to identify elusive causes, providing accurate diagnoses and informed prognoses for family planning and medical interventions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Kirk A. J. Stephenson, Julia Zhu, Adrian Dockery, Laura Whelan, Tomas Burke, Jacqueline Turner, James J. O'Byrne, G. Jane Farrar, David J. Keegan
Summary: Inherited retinal degenerations (IRDs) are a common cause of blindness in the working age population. Genetic testing plays a crucial role in diagnosing IRDs, with first-tier panel-based next-generation sequencing having a high success rate. This study demonstrates the reassessment of patients with negative results from first-tier testing and the effectiveness of second-tier genetic testing methods. By utilizing appropriate genetic testing techniques, the overall resolution rate of previously unresolved cases was increased to 92%. First-tier testing remains the most cost-effective approach, and second-tier testing should be guided by clinical and genetic indications to achieve a genetic diagnosis in a cost-effective manner.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Genetics & Heredity
Zeinab Fadaie, Laura Whelan, Tamar Ben-Yosef, Adrian Dockery, Zelia Corradi, Christian Gilissen, Lonneke Haer-Wigman, Jordi Corominas, Galuh D. N. Astuti, Laura de Rooij, L. Ingeborgh van den Born, Caroline C. W. Klaver, Carel B. Hoyng, Niamh Wynne, Emma S. Duignan, Paul F. Kenna, Frans P. M. Cremers, G. Jane Farrar, Susanne Roosing
Summary: Whole-genome sequencing was used to identify genetic causes in a cohort of inherited retinal disease patients, where coding variants and structural variants were observed. In addition, in vitro splice assays were utilized to detect pathogenic splice defects in rare variants.
NPJ GENOMIC MEDICINE
(2021)
Editorial Material
Medicine, General & Internal
Kit Green Sanderson, Kirk A. J. Stephenson, Adrian Dockery, David J. Keegan
Article
Genetics & Heredity
Julia Zhu, Kirk A. J. Stephenson, Adrian Dockery, Jacqueline Turner, James J. O'Byrne, Susan Fitzsimon, G. Jane Farrar, D. Ian Flitcroft, David J. Keegan
Summary: Inherited retinal degenerations (IRDs) account for a significant proportion of pediatric blindness, and there are often long delays in reaching a diagnosis. In this study, a telegenetics approach was used to offer genetic testing to children with phenotypic evidence of IRD during the COVID-19 pandemic. Genetic testing identified causative genetic variants in a high percentage of patients, and a significant proportion were eligible for approved therapies or clinical trial-based gene therapies. Early introduction of genetic testing is crucial for genetic counseling and preparation for upcoming gene therapy trials in pediatric IRD patients.
Article
Medicine, Research & Experimental
Arpad Palfi, Naomi Chadderton, Sophia Millington-Ward, Iris Post, Pete Humphries, Paul F. Kenna, G. Jane Farrar
Summary: In this study, the retinal utility of AAV-PHP.eB, a recently developed vector, was characterized in mice. The vector showed pan-retinal transduction, high efficiency in targeting photoreceptor and retinal pigment epithelium cells, and similar gene expression to AAV2/2.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2022)
Article
Oncology
Sophia Millington-Ward, Naomi Chadderton, Laura K. Finnegan, Iris J. M. Post, Matthew Carrigan, Tom Gardiner, Elisa Peixoto, Daniel Maloney, Marian M. Humphries, Alan Stitt, Thierry Leveillard, Pete Humphries, Paul F. Kenna, Arpad Palfi, G. Jane Farrar
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Laura K. Finnegan, Naomi Chadderton, Paul F. Kenna, Arpad Palfi, Michael Carty, Andrew G. Bowie, Sophia Millington-Ward, G. Jane Farrar
Summary: The challenge of developing gene therapies for genetic forms of blindness is heightened by the heterogeneity of these conditions. However, mechanistic commonalities indicate key pathways that may be targeted in a gene-independent approach. This study explores the neuroprotective effect of SARM1 ablation in a mouse model of retinal ganglion cell loss and visual dysfunction induced by rotenone. The results show that Sarm1 knockout mice retain visual function after rotenone insult and have significantly higher optokinetic response measurements than wild type mice. The protection of spatial vision is sustained over time and is accompanied by increased RGC survival and preservation of axonal density in the optic nerves. Fibroblasts from Sarm1 knockout mice demonstrate increased mitochondrial bioenergetics. These findings suggest that SARM1 ablation can increase mitochondrial function and provide histological and functional protection against mitochondrial dysfunction in the mouse retina.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)