scholarly journals Molecular Therapies for Choroideremia

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 738 ◽  
Author(s):  
Jasmina Cehajic Kapetanovic ◽  
Alun R. Barnard ◽  
Robert E. MacLaren
Keyword(s):  
Gene Therapy ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Phase Iii ◽  
Nonsense Suppression ◽  
Inherited Retinal Disease ◽  
Molecular Therapies ◽  
Restoration Strategies

Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several groundbreaking clinical studies that ultimately led to approval of Luxturna, the first gene therapy for an inherited retinal disease. In parallel, international research community has been engaged in conducting gene therapy trials for another more common inherited retinal disease known as choroideremia and with phase III clinical trials now underway, approval of this therapy is poised to follow suit. This chapter discusses new insights into clinical phenotyping and molecular genetic testing in choroideremia with review of molecular mechanisms implicated in its pathogenesis. We provide an update on current gene therapy trials and discuss potential inclusion of female carries in future clinical studies. Alternative molecular therapies are discussed including suitability of CRISPR gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroideremia.

scholarly journals Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with CNGA3-Associated Autosomal Recessive Achromatopsia

2021 ◽  
Vol 22 (15) ◽  
pp. 7842
Author(s):  
Susanne Kohl ◽  
Britta Baumann ◽  
Francesca Dassie ◽  
Anja K. Mayer ◽  
Maria Solaki ◽  
...  
Keyword(s):  
Segregation Analysis ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Underlying Mechanism ◽  
Recurrence Risk ◽  
Molecular Genetic Analysis ◽  
Recessive Mutation ◽  
Chromosome 2 ◽  
Inherited Retinal Disease ◽  
Uniparental Isodisomy

Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.

scholarly journals Methodological Challenges in the Economic Evaluation of a Gene Therapy for RPE65-Mediated Inherited Retinal Disease: The Value of Vision

2021 ◽  
Vol 39 (4) ◽  
pp. 383-397
Author(s):  
Simone A. Huygens ◽  
Matthijs M. Versteegh ◽  
Stefan Vegter ◽  
L. Jan Schouten ◽  
Tim A. Kanters
Keyword(s):  
Gene Therapy ◽  
Economic Evaluation ◽  
Retinal Disease ◽  
Inherited Retinal Disease ◽  
Methodological Challenges

Genes and Gene Therapy in Inherited Retinal Disease

2021 ◽  
Vol 61 (4) ◽  
pp. 3-45
Author(s):  
Aumer Shughoury ◽  
Thomas A. Ciulla ◽  
Benjamin Bakall ◽  
Mark E. Pennesi ◽  
Szilárd Kiss ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinal Disease ◽  
Inherited Retinal Disease

scholarly journals Induced Pluripotent Stem Cells and Outer Retinal Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Jin Yang ◽  
Bingcui Cai ◽  
Patrick Glencer ◽  
Zhiqing Li ◽  
Xiaomin Zhang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Posterior Part ◽  
Retinal Disease ◽  
Retinal Cell ◽  
Cell Transplant ◽  
Blood Retinal Barrier ◽  
First Choice

The retina, which is composed of multiple layers of differing cell types, has been considered the first choice for gene therapy, disease modeling, and stem cell-derived retinal cell transplant therapy. Because of its special characteristics, the retina, located in the posterior part of the eye, can be well observed directly after gene therapy or transplantation. The blood-retinal barrier is part of a specialized ocular microenvironment that is immune privileged. This protects transplanted cells and tissue. Having two eyes makes perfect natural control possible after a single eye receives gene or stem cell therapy. For this reason, research about exploring retinal diseases’ underlying molecular mechanisms and potential therapeutic approach using stem cell technique has been developing rapidly. This review is to present an up-to-date summary of the iPSC’s sources, variations, differentiation methods, and the wide-ranging application of iPSCs-RPCS or iPSCs-RPE on retinal disease modeling, diagnostics, and therapeutics.

scholarly journals 89 Five-year update for the Phase III voretigene neparvovec study in biallelic RPE65 mutation–associated inherited retinal disease

2021 ◽  
Author(s):  
Bart P Leroy ◽  
Stephen R Russell ◽  
Jean Bennett ◽  
Katherine A High ◽  
Arlene V Drack ◽  
...  
Keyword(s):  
Retinal Disease ◽  
Phase Iii ◽  
Inherited Retinal Disease

scholarly journals Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Anna Skorczyk-Werner ◽  
Zuzanna Niedziela ◽  
Marcin Stopa ◽  
Maciej Robert Krawczyński
Keyword(s):  
Gene Therapy ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Severe Form ◽  
Gene Variants ◽  
Genetic Characteristics ◽  
Leber Congenital Amaurosis ◽  
Pathogenic Variants ◽  
Intronic Mutation ◽  
Novel Variants

Abstract Background Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families. Methods Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families. Results The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group. Conclusions This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.

Gene Therapy, Diet and Drug Approaches to Treating Inherited Retinal Disease

2021 ◽  
Author(s):  
Matthew P. Simunovic ◽  
Heather G. Mack ◽  
Lauren N. Ayton ◽  
Mark M. Hassall
Keyword(s):  
Gene Therapy ◽  
Retinal Disease ◽  
Inherited Retinal Disease
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