Gene Therapy in Hereditary Retinal Dystrophies: The Usefulness of Diagnostic Tools in Candidate Patient Selections

Purpose: Gene therapy actually seems to have promising results in the treatment of Leber Congenital Amaurosis and some different inherited retinal diseases (IRDs); the primary goal of this strategy is to change gene defects with a wild-type gene without defects in a DNA sequence to achieve partial recovery of the photoreceptor function and, consequently, partially restore lost retinal functions. This approach led to the introduction of a new drug (voretigene neparvovec-rzyl) for replacement of the RPE65 gene in patients affected by Leber Congenital Amaurosis (LCA); however, the treatment results are inconstant and with variable long-lasting effects due to a lack of correctly evaluating the anatomical and functional conditions of residual photoreceptors. These variabilities may also be related to host immunoreactive reactions towards the Adenovirus-associated vector. A broad spectrum of retinal dystrophies frequently generates doubt as to whether the disease or the patient is a good candidate for a successful gene treatment, because, very often, different diseases share similar genetic characteristics, causing an inconstant genotype/phenotype correlation between clinical characteristics also within the same family. For example, mutations on the RPE65 gene cause Leber Congenital Amaurosis (LCA) but also some forms of Retinitis Pigmentosa (RP), Bardet Biedl Syndrome (BBS), Congenital Stationary Night Blindness (CSNB) and Usher syndrome (USH), with a very wide spectrum of clinical manifestations. These confusing elements are due to the different pathways in which the product protein (retinoid isomer-hydrolase) is involved and, consequently, the overlapping metabolism in retinal function. Considering this point and the cost of the drug (over USD one hundred thousand), it would be mandatory to follow guidelines or algorithms to assess the best-fitting disease and candidate patients to maximize the output. Unfortunately, at the moment, there are no suggestions regarding who to treat with gene therapy. Moreover, gene therapy might be helpful in other forms of inherited retinal dystrophies, with more frequent incidence of the disease and better functional conditions (actually, gene therapy is proposed only for patients with poor vision, considering possible side effects due to the treatment procedures), in which this approach leads to better function and, hopefully, visual restoration. But, in this view, who might be a disease candidate or patient to undergo gene therapy, in relationship to the onset of clinical trials for several different forms of IRD? Further, what is the gold standard for tests able to correctly select the patient? Our work aims to evaluate clinical considerations on instrumental morphofunctional tests to assess candidate subjects for treatment and correlate them with clinical and genetic defect analysis that, often, is not correspondent. We try to define which parameters are an essential and indispensable part of the clinical rationale to select patients with IRDs for gene therapy. This review will describe a series of models used to characterize retinal morphology and function from tests, such as optical coherence tomography (OCT) and electrophysiological evaluation (ERG), and its evaluation as a primary outcome in clinical trials. A secondary aim is to propose an ancillary clinical classification of IRDs and their accessibility based on gene therapy’s current state of the art. Material and Methods: OCT, ERG, and visual field examinations were performed in different forms of IRDs, classified based on clinical and retinal conditions; compared to the gene defect classification, we utilized a diagnostic algorithm for the clinical classification based on morphofunctional information of the retina of patients, which could significantly improve diagnostic accuracy and, consequently, help the ophthalmologist to make a correct diagnosis to achieve optimal clinical results. These considerations are very helpful in selecting IRD patients who might respond to gene therapy with possible therapeutic success and filter out those in which treatment has a lower chance or no chance of positive results due to bad retinal conditions, avoiding time-consuming patient management with unsatisfactory results.

[1]  M. Repka,et al.  Amblyopia Preferred Practice Pattern®. , 2022, Ophthalmology.

[2]  Hane Lee,et al.  Congenital Stationary Night Blindness: Clinical and Genetic Features , 2022, International journal of molecular sciences.

[3]  N. Parry,et al.  Retinal gene therapy in RPE-65 gene mediated inherited retinal dystrophy , 2022, Eye.

[4]  D. Bosnar,et al.  RPE65 c.353G>A, p.(Arg118Lys): A Novel Point Mutation Associated with Retinitis Pigmentosa and Macular Atrophy , 2022, International journal of molecular sciences.

[5]  V. Sheffield,et al.  Progressive retinal degeneration of rods and cones in a Bardet-Biedl syndrome type 10 mouse model , 2022, Disease models & mechanisms.

[6]  J. Ruiz-Ederra,et al.  Subretinal Injection Techniques for Retinal Disease: A Review , 2022, Journal of clinical medicine.

[7]  E. Zrenner,et al.  Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort , 2022, Genes.

[8]  P. Melillo,et al.  RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study , 2022, Investigative ophthalmology & visual science.

[9]  T. Aleman,et al.  Comparative Natural History of Visual Function From Patients With Biallelic Variants in BBS1 and BBS10 , 2021, Investigative ophthalmology & visual science.

[10]  Chang-Hao Yang,et al.  Leber’s Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations , 2021, Genes.

[11]  K. Xue,et al.  Characterizing the cellular immune response to subretinal AAV gene therapy in the murine retina , 2021, Molecular therapy. Methods & clinical development.

[12]  S. Woo,et al.  Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients , 2021, Genes.

[13]  I. Buño,et al.  Novel biallelic variant in BBS9 causative of Bardet–Biedl syndrome: expanding the spectrum of disease-causing genetic alterations , 2021, BMC medical genomics.

[14]  Xiaohong Meng,et al.  Ocular Characteristics of Patients With Bardet–Biedl Syndrome Caused by Pathogenic BBS Gene Variation in a Chinese Cohort , 2021, Frontiers in Cell and Developmental Biology.

[15]  Z. Tümer,et al.  BBS Proteins Affect Ciliogenesis and Are Essential for Hedgehog Signaling, but Not for Formation of iPSC-Derived RPE-65 Expressing RPE-Like Cells , 2021, International journal of molecular sciences.

[16]  K. Ahmad,et al.  Congenital stationary night blindness: an update and review of the disease spectrum in Saudi Arabia , 2020, Acta ophthalmologica.

[17]  S. Tsang,et al.  Gene therapy for inherited retinal diseases , 2020, Annals of translational medicine.

[18]  T. Aleman,et al.  Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy. , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  Sumit Kumar,et al.  Multiple retinal astrocytic hamartomas in siblings with lebers congenital amaurosis: a case series and review of literature , 2020, BMC Ophthalmology.

[20]  S. Tsang,et al.  Optical coherence tomography in the evaluation of retinitis pigmentosa , 2020, Ophthalmic genetics.

[21]  Denise J. Pearson,et al.  Treatment Potential for LCA5-Associated Leber Congenital Amaurosis , 2020, Investigative ophthalmology & visual science.

[22]  B. Lujan,et al.  Retinal gene therapy in X-linked retinitis pigmentosa caused by mutations in RPGR: Results at 6 months in a first in human clinical trial , 2020, Nature Medicine.

[23]  Yihua Zhu,et al.  The effect of human gene therapy for RPE65-associated Leber’s congenital amaurosis on visual function: a systematic review and meta-analysis , 2020, Orphanet Journal of Rare Diseases.

[24]  C. Méndez-Vidal,et al.  Unmasking Retinitis Pigmentosa complex cases by a whole genome sequencing algorithm based on open-access tools: hidden recessive inheritance and potential oligogenic variants , 2020, Journal of Translational Medicine.

[25]  W. Hauswirth,et al.  Long-Term Structural Outcomes of Late-Stage RPE65 Gene Therapy. , 2020, Molecular therapy : the journal of the American Society of Gene Therapy.

[26]  Kathleen A. Marshall,et al.  Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. , 2019, Ophthalmology.

[27]  M. McCall,et al.  Presynaptic Expression of LRIT3 Transsynaptically Organizes the Postsynaptic Glutamate Signaling Complex Containing TRPM1 , 2019, Cell reports.

[28]  D. Gesellschaft,et al.  Stellungnahme von DOG, RG und BVA zur therapeutischen Anwendung von voretigene neparvovec (Luxturna™) in der Augenheilkunde , 2019, Der Ophthalmologe.

[29]  P. Mathur,et al.  Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina , 2019, Hearing Research.

[30]  M. Nakazawa,et al.  The findings of optical coherence tomography of retinal degeneration in relation to the morphological and electroretinographic features in RPE65−/− mice , 2019, PloS one.

[31]  B. J. Klevering,et al.  Non-syndromic retinitis pigmentosa , 2018, Progress in Retinal and Eye Research.

[32]  Sieu K. Khuu,et al.  Optical treatment of amblyopia: a systematic review and meta‐analysis , 2018, Clinical & experimental optometry.

[33]  B. Wilhelm,et al.  Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients. , 2018, Investigative ophthalmology & visual science.

[34]  B. Wilhelm,et al.  Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates. , 2017, Investigative ophthalmology & visual science.

[35]  P. Campochiaro,et al.  The mechanism of cone cell death in Retinitis Pigmentosa , 2017, Progress in Retinal and Eye Research.

[36]  Kathleen A. Marshall,et al.  Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial , 2017, The Lancet.

[37]  M. Michaelides,et al.  Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions , 2017, British Journal of Ophthalmology.

[38]  S. Halford,et al.  Unravelling the genetics of inherited retinal dystrophies: Past, present and future , 2017, Progress in Retinal and Eye Research.

[39]  H. Ahn,et al.  Prevalence, Age at Diagnosis, Mortality, and Cause of Death in Retinitis Pigmentosa in Korea-A Nationwide Population-based Study. , 2017, American journal of ophthalmology.

[40]  B. Hafler CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING , 2017, Retina.

[41]  T. Hohman,et al.  Hereditary Retinal Dystrophy. , 2016, Handbook of experimental pharmacology.

[42]  G. Liew,et al.  Retinitis pigmentosa-associated cystoid macular oedema: pathogenesis and avenues of intervention , 2016, British Journal of Ophthalmology.

[43]  S. Nampoothiri,et al.  Bardet–Biedl syndrome: Genetics, molecular pathophysiology, and disease management , 2016, Indian journal of ophthalmology.

[44]  Jean Bennett,et al.  Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial , 2016, The Lancet.

[45]  David J. Wilson,et al.  Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. , 2016, Ophthalmology.

[46]  Fang Wang,et al.  Optical Coherence Tomographic Analysis of Retina in Retinitis Pigmentosa Patients , 2016, Ophthalmic Research.

[47]  Rick Tearle,et al.  Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease , 2016, Ophthalmology.

[48]  V. Sheffield,et al.  Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). , 2016, Human molecular genetics.

[49]  Dongli Yang,et al.  N-Acetylcysteine Amide Protects Against Oxidative Stress–Induced Microparticle Release From Human Retinal Pigment Epithelial Cells , 2016, Investigative ophthalmology & visual science.

[50]  W. Hauswirth,et al.  Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial , 2016, Human Genetics.

[51]  Rémy Bruggmann,et al.  Clinical sequencing: is WGS the better WES? , 2016, Human Genetics.

[52]  E. Strettoi,et al.  Pharmacological approaches to retinitis pigmentosa: A laboratory perspective , 2015, Progress in Retinal and Eye Research.

[53]  E. Simpson,et al.  Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness. , 2015, Human molecular genetics.

[54]  G. Holder,et al.  Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome. , 2015, American journal of ophthalmology.

[55]  Y. Huang,et al.  BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors , 2015, Scientific Reports.

[56]  J. Chiang,et al.  The current status of molecular diagnosis of inherited retinal dystrophies , 2015, Current opinion in ophthalmology.

[57]  S. E. Barker,et al.  Long-term effect of gene therapy on Leber's congenital amaurosis. , 2015, The New England journal of medicine.

[58]  A. J. Roman,et al.  Improvement in vision: a new goal for treatment of hereditary retinal degenerations , 2015, Expert opinion on orphan drugs.

[59]  Anthony G. Robson,et al.  Congenital stationary night blindness: An analysis and update of genotype–phenotype correlations and pathogenic mechanisms , 2015, Progress in Retinal and Eye Research.

[60]  J. Sahel,et al.  Clinical characteristics and current therapies for inherited retinal degenerations. , 2015, Cold Spring Harbor perspectives in medicine.

[61]  J. Bennett,et al.  The Status of RPE65 Gene Therapy Trials: Safety and Efficacy. , 2015, Cold Spring Harbor perspectives in medicine.

[62]  D. Hood,et al.  A comparison of progressive loss of the ellipsoid zone (EZ) band in autosomal dominant and x-linked retinitis pigmentosa. , 2014, Investigative ophthalmology & visual science.

[63]  Ken Ogino,et al.  PREVALENCE AND SPATIAL DISTRIBUTION OF CYSTOID SPACES IN RETINITIS PIGMENTOSA: Investigation With Spectral Domain Optical Coherence Tomography , 2014, Retina.

[64]  R. MacLaren,et al.  Evaluation of an Optimized Injection System for Retinal Gene Therapy in Human Patients. , 2014, Human gene therapy methods.

[65]  Masayuki Hata,et al.  Intraretinal hyperreflective foci on spectral-domain optical coherence tomographic images of patients with retinitis pigmentosa. , 2014, Clinical ophthalmology.

[66]  G. La Torre,et al.  Dorzolamide Chlorhydrate Versus Acetazolamide in the Management of Chronic Macular Edema in Patients with Retinitis Pigmentosa: Description of Three Case Reports , 2014, Ophthalmology and eye diseases.

[67]  Jacqueline Pei,et al.  Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements , 2013, Human Genetics.

[68]  S. Tsang,et al.  OUTER RETINAL TUBULATION IN DEGENERATIVE RETINAL DISORDERS , 2013, Retina.

[69]  Astrid M L Kappers,et al.  Genotype and phenotype of 101 dutch patients with congenital stationary night blindness. , 2013, Ophthalmology.

[70]  Makoto Nakamura,et al.  Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene , 2013, Proceedings of the National Academy of Sciences.

[71]  D. Hood,et al.  Spectral-domain optical coherence tomography measures of outer segment layer progression in patients with X-linked retinitis pigmentosa. , 2013, JAMA ophthalmology.

[72]  M. Parodi,et al.  Spectral Domain Optical Coherence Tomography Findings in Patients with Retinitis Pigmentosa , 2013, Ophthalmic Research.

[73]  E. Zrenner,et al.  Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies , 2013, European Journal of Human Genetics.

[74]  Y. Kim,et al.  Correlations between spectral-domain OCT measurements and visual acuity in cystoid macular edema associated with retinitis pigmentosa. , 2013, Investigative ophthalmology & visual science.

[75]  Alexander Sumaroka,et al.  Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement , 2013, Proceedings of the National Academy of Sciences.

[76]  J. Jonas,et al.  Prevalence of retinitis pigmentosa in India: the Central India Eye and Medical Study , 2012, Acta ophthalmologica.

[77]  Jinghua Hu,et al.  The BBSome controls IFT assembly and turnaround in cilia , 2012, Nature Cell Biology.

[78]  P. Beales,et al.  Bardet–Biedl syndrome , 2012, European Journal of Human Genetics.

[79]  A. Moore,et al.  Educational paper , 2012, European Journal of Pediatrics.

[80]  Kathleen A. Marshall,et al.  AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness , 2012, Science Translational Medicine.

[81]  J. Vandesompele,et al.  Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis , 2012, Genetics in Medicine.

[82]  William J Feuer,et al.  Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. , 2012, Archives of ophthalmology.

[83]  A. J. Roman,et al.  Retinal disease course in Usher syndrome 1B due to MYO7A mutations. , 2011, Investigative ophthalmology & visual science.

[84]  F. Parmeggiani,et al.  Clinical and Rehabilitative Management of Retinitis Pigmentosa: Up-to-Date , 2011, Current genomics.

[85]  S. Ferrari,et al.  Retinitis Pigmentosa: Genes and Disease Mechanisms , 2011, Current genomics.

[86]  V. Sheffield,et al.  Genomics and the eye. , 2011, The New England journal of medicine.

[87]  A. Berezovsky,et al.  Visual acuity and retinal function in patients with Bardet-Biedl syndrome , 2011, Clinics.

[88]  K. Steel,et al.  The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65 , 2011, Human molecular genetics.

[89]  Fiona Blanco-Kelly,et al.  An Update on the Genetics of Usher Syndrome , 2010, Journal of ophthalmology.

[90]  T. de Ravel,et al.  Genetic Screening of LCA in Belgium: Predominance of CEP290 and Identification of Potential Modifier Alleles in AHI1 of CEP290-related Phenotypes , 2010, Human mutation.

[91]  Artur V. Cideciyan,et al.  Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy , 2010, Progress in Retinal and Eye Research.

[92]  G. Pazour,et al.  Ablation of Whirlin Long Isoform Disrupts the USH2 Protein Complex and Causes Vision and Hearing Loss , 2010, PLoS genetics.

[93]  V. Sheffield,et al.  Bardet‐Biedl syndrome in Denmark—report of 13 novel sequence variations in six genes , 2010, Human mutation.

[94]  E. Rubel,et al.  Deafness and retinal degeneration in a novel USH1C knock‐in mouse model , 2010, Developmental neurobiology.

[95]  Madeline A. Lancaster,et al.  AHI1 is required for outer segment development and is a modifier for retinal degeneration in nephronophthisis , 2010, Nature Genetics.

[96]  Jean Bennett,et al.  Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[97]  J. Sahel,et al.  Genotyping microarray for CSNB-associated genes. , 2009, Investigative ophthalmology & visual science.

[98]  Kathleen A. Marshall,et al.  Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial , 2009, The Lancet.

[99]  M. Marra,et al.  Massively parallel sequencing: the next big thing in genetic medicine. , 2009, American journal of human genetics.

[100]  Kelly Shintani,et al.  Review and update: current treatment trends for patients with retinitis pigmentosa. , 2009, Optometry.

[101]  A. J. Roman,et al.  Disease boundaries in the retina of patients with Usher syndrome caused by MYO7A gene mutations. , 2009, Investigative ophthalmology & visual science.

[102]  M. Bitner-Glindzicz,et al.  Update on Usher syndrome , 2009, Current opinion in neurology.

[103]  M. Bach,et al.  ISCEV Standard for full-field clinical electroretinography (2008 update) , 2009, Documenta Ophthalmologica.

[104]  Edwin M Stone,et al.  Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics , 2008, Proceedings of the National Academy of Sciences.

[105]  A. J. Roman,et al.  Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. , 2008, Human molecular genetics.

[106]  Nick Tyler,et al.  Effect of gene therapy on visual function in Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[107]  Kathleen A. Marshall,et al.  Safety and efficacy of gene transfer for Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[108]  David S. Williams Usher syndrome: Animal models, retinal function of Usher proteins, and prospects for gene therapy , 2008, Vision Research.

[109]  Dorothy A. Thompson,et al.  An assessment of the apex microarray technology in genotyping patients with Leber congenital amaurosis and early-onset severe retinal dystrophy. , 2007, Investigative ophthalmology & visual science.

[110]  R. Wilke,et al.  Mutation screening of 299 Spanish families with retinal dystrophies by Leber congenital amaurosis genotyping microarray. , 2007, Investigative ophthalmology & visual science.

[111]  A. J. Roman,et al.  Inner retinal abnormalities in X-linked retinitis pigmentosa with RPGR mutations. , 2007, Investigative ophthalmology & visual science.

[112]  Christina Zeitz,et al.  Night blindness–associated mutations in the ligand‐binding, cysteine‐rich, and intracellular domains of the metabotropic glutamate receptor 6 abolish protein trafficking , 2007, Human mutation.

[113]  D. S. Williams,et al.  Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B , 2007, Gene Therapy.

[114]  R. Lewis,et al.  BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus , 2006, Nature Genetics.

[115]  J. Cruysberg,et al.  Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. , 2006, Investigative ophthalmology & visual science.

[116]  T. Aleman,et al.  Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[117]  Steve D. M. Brown,et al.  Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population , 2005, Human Genetics.

[118]  Edward N. Pugh,et al.  From candelas to photoisomerizations in the mouse eye by rhodopsin bleaching in situ and the light-rearing dependence of the major components of the mouse ERG , 2004, Vision Research.

[119]  R. Allikmets Leber congenital amaurosis: a genetic paradigm , 2004, Ophthalmic genetics.

[120]  David S. Williams,et al.  Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[121]  B. Lorenz,et al.  Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. , 2003, Investigative ophthalmology & visual science.

[122]  David S. Williams,et al.  Actin-based motor properties of native myosin VIIa. , 2002, Journal of cell science.

[123]  S. Jacobson,et al.  Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa , 2000, Nature Genetics.

[124]  G. Fishman,et al.  Patterns of visual field progression in patients with retinitis pigmentosa. , 1998, Ophthalmology.

[125]  A. Milam,et al.  Histopathology of the human retina in retinitis pigmentosa. , 1998, Progress in retinal and eye research.

[126]  G. Hitman,et al.  Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. , 1997, Journal of medical genetics.

[127]  Steve D. M. Brown,et al.  Defective myosin VIIA gene responsible for Usher syndrome type IB , 1995, Nature.

[128]  A. Hendrickson,et al.  Human photoreceptor topography , 1990, The Journal of comparative neurology.

[129]  S Berman,et al.  Retinal damage by light in rats. , 1966, Investigative ophthalmology.

[130]  L. Riggs Electroretinography in cases of night blindness. , 1954, American journal of ophthalmology.

[131]  G. Schubert,et al.  Beitrag zur Analyse des menschlichen Elektroretinogramms , 1952 .

[132]  F. Cremers,et al.  Identification and Analysis of Genes Associated with Inherited Retinal Diseases. , 2019, Methods in molecular biology.

[133]  A. Cideciyan,et al.  Leber Congenital Amaurosis: Genotypes and Retinal Structure Phenotypes. , 2016, Advances in experimental medicine and biology.

[134]  Donald C Hood,et al.  The transition zone between healthy and diseased retina in patients with retinitis pigmentosa. , 2011, Investigative ophthalmology & visual science.

[135]  J. Heckenlively,et al.  Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy , 2004, Nature Genetics.

[136]  R. A. Pagon,et al.  Retinitis pigmentosa. , 1988, Survey of ophthalmology.