-
Molecular Therapy : the Journal of the... Feb 2021Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers... (Review)
Review
Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency [ADA-SCID] in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy [SMA]; Duchenne muscular dystrophy [DMD]; X-linked myotubular myopathy [XLMTM]; and diseases of the central nervous system, including Alzheimer's disease, Parkinson's disease, Canavan disease, aromatic l-amino acid decarboxylase [AADC] deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration [AMD], choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.
Topics: Animals; Clinical Studies as Topic; Combined Modality Therapy; Dependovirus; Gene Expression; Genetic Diseases, Inborn; Genetic Therapy; Genetic Vectors; Humans; Organ Specificity; Treatment Outcome
PubMed: 33309881
DOI: 10.1016/j.ymthe.2020.12.007 -
Biomolecules Aug 2021Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for... (Review)
Review
Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide.
Topics: Animals; Cell Line; Child; Clinical Trials as Topic; Gene Editing; Genetic Therapy; Humans; Mice; Stargardt Disease
PubMed: 34439845
DOI: 10.3390/biom11081179 -
Progress in Retinal and Eye Research May 2021X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic... (Review)
Review
X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.
Topics: Calcium Channels, L-Type; Eye Proteins; Female; Genes, X-Linked; Genetic Diseases, X-Linked; Humans; Male; Mutation; Night Blindness; Phenotype; Retinal Degeneration
PubMed: 32860923
DOI: 10.1016/j.preteyeres.2020.100898 -
American Journal of Human Genetics Jan 2017Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of...
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
Topics: Adaptor Proteins, Signal Transducing; Alleles; Base Sequence; Choroideremia; DNA Mutational Analysis; Ethnicity; Exome; Female; Genes, Recessive; Genetic Variation; Genome, Human; Humans; Introns; Male; Mutation; Rare Diseases; Retinal Diseases
PubMed: 28041643
DOI: 10.1016/j.ajhg.2016.12.003 -
Progress in Retinal and Eye Research Nov 2022Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of macular cystoid spaces referred to as non-vasogenic cystoid maculopathies (NVCM)... (Review)
Review
Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of macular cystoid spaces referred to as non-vasogenic cystoid maculopathies (NVCM) may be detected on optical coherence tomography but not on fluorescein angiography. Various causes may disrupt retinal cell cohesion or impair retinal pigment epithelium (RPE) and Müller cell functions in the maintenance of retinal dehydration, resulting in cystoid spaces formation. Tractional causes include vitreomacular traction, epiretinal membranes and myopic foveoschisis. Surgical treatment does not always allow cystoid space resorption. In inherited retinal dystrophies, cystoid spaces may be part of the disease as in X-linked retinoschisis or enhanced S-cone syndrome, or occur occasionally as in bestrophinopathies, retinitis pigmentosa and allied diseases, congenital microphthalmia, choroideremia, gyrate atrophy and Bietti crystalline dystrophy. In macular telangiectasia type 2, cystoid spaces and cavitations do not depend on the fluid leakage from telangiectasia. Various causes affecting RPE function may result in NVCM such as chronic central serous chorioretinopathy and paraneoplastic syndromes. Non-exudative age macular degeneration may also be complicated by intraretinal cystoid spaces in the absence of fluorescein leakage. In these diseases, cystoid spaces occur in a context of retinal cell loss. Various causes of optic atrophy, including open-angle glaucoma, result in microcystoid spaces in the inner nuclear layer due to a retrograde transsynaptic degeneration. Lastly, drug toxicity may also induce cystoid maculopathy. Identifying NVCM on multimodal imaging, including fluorescein angiography if needed, allows guiding the diagnosis of the causative disease and choosing adequate treatment when available.
Topics: Humans; Glaucoma, Open-Angle; Macular Edema; Fluorescein Angiography; Macular Degeneration; Tomography, Optical Coherence; Retinal Telangiectasis
PubMed: 35927124
DOI: 10.1016/j.preteyeres.2022.101092 -
Genes Sep 2019Advances in molecular research have culminated in the development of novel gene-based therapies for inherited retinal diseases. We have recently witnessed several... (Review)
Review
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 gene editing, small molecule nonsense suppression therapy and vision restoration strategies in late stage choroideremia.
Topics: Animals; Choroideremia; Genetic Therapy; Genotype; Humans; Phenotype
PubMed: 31548516
DOI: 10.3390/genes10100738 -
BMC Medical Genomics Mar 2021To date, no genetic analysis of inherited retinal disease (IRD) using whole-exome sequencing (WES) has been conducted in a large-scale Korean cohort. The aim of this...
BACKGROUND
To date, no genetic analysis of inherited retinal disease (IRD) using whole-exome sequencing (WES) has been conducted in a large-scale Korean cohort. The aim of this study was to characterise the genetic profile of IRD patients in Korea using WES.
METHODS
We performed comprehensive molecular testing in 168 unrelated Korean IRD patients using WES. The potential pathogenicity of candidate variants was assessed using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant interpretation guidelines, in silico prediction tools, published literature, and compatibility with known phenotypes or inheritance patterns.
RESULTS
Causative variants were detected in 86/168 (51.2%) IRD patients, including 58/107 (54.2%) with retinitis pigmentosa, 7/15 (46.7%) with cone and cone-rod dystrophy, 2/3 (66.6%) with Usher syndrome, 1/2 (50.0%) with congenital stationary night blindness, 2/2 (100.0%) with Leber congenital amaurosis, 1/1 (100.0%) with Bietti crystalline dystrophy, 1/1 (100.0%) with Joubert syndrome, 9/10 (90.0%) with Stargardt macular dystrophy, 1/10 (10.0%) with vitelliform macular dystrophy, 1/11 (9.1%) with other forms of macular dystrophy, and 3/4 (75.0%) with choroideraemia. USH2A, ABCA4, and EYS were the most common causative genes associated with IRD. For retinitis pigmentosa, variants of USH2A and EYS were the most common causative gene mutations.
CONCLUSIONS
This study demonstrated the distribution of causative genetic mutations in Korean IRD patients. The data will serve as a reference for future genetic screening and development of treatment modalities for Korean IRD patients.
Topics: Adult; Humans; Male; Republic of Korea; Retinal Dystrophies; Retinitis Pigmentosa; Exome Sequencing
PubMed: 33691693
DOI: 10.1186/s12920-021-00874-6 -
International Journal of Molecular... Sep 2023Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration... (Review)
Review
Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.
Topics: Child; Adolescent; Humans; Choroideremia; Choroid; Night Blindness; Fovea Centralis; Genetic Therapy
PubMed: 37762657
DOI: 10.3390/ijms241814354 -
Advances in Experimental Medicine and... 2019Choroideremia (CHM) is associated with progressive degeneration of the retinal pigment epithelium (RPE), choriocapillaris (CC), and photoreceptors. As animal models of... (Review)
Review
Choroideremia (CHM) is associated with progressive degeneration of the retinal pigment epithelium (RPE), choriocapillaris (CC), and photoreceptors. As animal models of CHM are lacking, most information about cell survival has come from imaging affected patients. This chapter discusses a combination of imaging techniques, including fundus-guided microperimetry, confocal and non-confocal adaptive optics scanning laser ophthalmoscopy (AOSLO), fundus autofluorescence (FAF), and swept-source optical coherence tomography angiography (SS-OCTA) to analyze macular sensitivity, cone photoreceptor outer and inner segment structure, RPE structure, and CC perfusion, respectively. Combined imaging modalities such as those described here can provide sensitive measures of monitoring retinal structure and function in patients with CHM.
Topics: Angiography; Animals; Choroid; Choroideremia; Humans; Multimodal Imaging; Ophthalmoscopy; Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Retinal Pigment Epithelium; Tomography, Optical Coherence
PubMed: 31884602
DOI: 10.1007/978-3-030-27378-1_23