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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 -
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 -
The British Journal of Ophthalmology Apr 2020Macular dystrophies (MDs) consist of a heterogeneous group of disorders that are characterised by bilateral symmetrical central visual loss. Advances in genetic testing... (Review)
Review
Macular dystrophies (MDs) consist of a heterogeneous group of disorders that are characterised by bilateral symmetrical central visual loss. Advances in genetic testing over the last decade have led to improved knowledge of the underlying molecular basis. The developments in high-resolution multimodal retinal imaging have also transformed our ability to make accurate and more timely diagnoses and more sensitive quantitative assessment of disease progression, and allowed the design of optimised clinical trial endpoints for novel therapeutic interventions. The aim of this review was to provide an update on MDs, including Stargardt disease, Best disease, X-linked r etinoschisis, pattern dystrophy, Sorsby fundus dystrophy and autosomal dominant drusen. It highlights the range of innovations in retinal imaging, genotype-phenotype and structure-function associations, animal models of disease and the multiple treatment strategies that are currently in clinical trial or planned in the near future, which are anticipated to lead to significant changes in the management of patients with MDs.
Topics: Diagnostic Imaging; Humans; Macular Degeneration; Molecular Biology; Therapeutics
PubMed: 31704701
DOI: 10.1136/bjophthalmol-2019-315086 -
Eye (London, England) Sep 2021First described by Gaucher and associates in 2008 in eyes with high myopia, dome-shaped maculopathy (DSM) is an anterior convex protrusion of the macula towards the... (Review)
Review
First described by Gaucher and associates in 2008 in eyes with high myopia, dome-shaped maculopathy (DSM) is an anterior convex protrusion of the macula towards the vitreous cavity observable on OCT. This seems to be related to a localized scleral thickness, which might be the result of regional variation in the scleral bio-mechanical properties and the process of emmetropization causing asymmetric scleral growth. The presence of DSM can be associated with an increased risk of complications. The clinical spectrum ranges from being asymptomatic to metamorphopsia and mild-to-moderate gradual visual loss over years. Visual impairment in DSM results from retinal pigment epithelial changes, sub-foveal serous detachment, retinoschisis and myopic choroidal neovascularization. In this review, we compile and review the available information on the pathophysiology, nomenclature, classification, clinical features including imaging, differential diagnosis, complications associated with DSM and the gaps in our understanding of this entity thus far.
Topics: Fluorescein Angiography; Humans; Macula Lutea; Macular Degeneration; Myopia, Degenerative; Retinal Diseases; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity
PubMed: 33875828
DOI: 10.1038/s41433-021-01518-w -
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 -
Tzu Chi Medical Journal 2022Hereditary retinal dystrophies (HRDs), such as retinitis pigmentosa, Leber's congenital amaurosis (LCA), Usher syndrome, and retinoschisis, are a group of genetic... (Review)
Review
Hereditary retinal dystrophies (HRDs), such as retinitis pigmentosa, Leber's congenital amaurosis (LCA), Usher syndrome, and retinoschisis, are a group of genetic retinal disorders exhibiting both genetic and phenotypic heterogeneity. Symptoms include progressive retinal degeneration and constricted visual field. Some patients will be legal or completely blind. Advanced sequencing technologies improve the genetic diagnosis of HRD and lead to a new era of research into gene-targeted therapies. Following the first Food and Drug Administration approval of gene augmentation therapy for LCA caused by mutations, multiple clinical trials are currently underway applying different techniques. In this review, we provide an overview of gene therapy for HRD and emphasize four distinct approaches to gene-targeted therapy that have the potential to slow or even reverse retinal degeneration: (1) viral vector-based and nonviral gene delivery, (2) RNA-based antisense oligonucleotide, (3) genome editing by the Clustered Regularly Interspaced Short Palindromic Repeat/cas9 system, and (4) optogenetics gene therapy.
PubMed: 36578644
DOI: 10.4103/tcmj.tcmj_78_22 -
The Pan African Medical Journal 2019Best's disease is an inherited macular dystrophy with autosomal dominant inheritance pattern, characterized by the presence of autofluorescent vitelliform deposition...
Best's disease is an inherited macular dystrophy with autosomal dominant inheritance pattern, characterized by the presence of autofluorescent vitelliform deposition whose development is stereotyped from its manifestation to the fragmentation of the material and then to its resorption. Age at onset is between 7 and 12 years. Except in the presence of complications, patients are more often asymptomatic and the disease is discovered fortuitously. We report the case of 8 year-old only daughter with no particular past medical history. Ophthalmologic examination showed corrected visual acuity 7/10 in the left and right eyes, the examination of the anterior segment was normal, fundus examination showed macular yellowish-white stain (A, B). On fluorescein angiography, hyperfluorescence occurred early followed by a hypofluorescence. Macular imaging by optical coherence tomography (OCT) showed the presence of an empty optical space between the neuroretina and the pigment epithelium (C, D). Assessment was performed: electrooculogram was perturbed using Arden ratio of 146% in the right eye and 179% in the left eye. Electroretinogram, visual fields and color vision test were normal. Fundus examination of parents was normal. The diagnosis of previtelliform BEST's disease was made based on early hypofluorescence, OCT appearance and alteration of the electroretinogram. Differential diagnoses included: stargardt's disease, progressive dystrophy of the cones and X-linked retinoschisis. No treatment was proposed, only simple monitoring.
PubMed: 31762926
DOI: 10.11604/pamj.2019.34.61.19771 -
Clinical & Experimental Optometry Sep 2020Retinoschisis can be found in the fovea or the retinal periphery, either of which may be present in isolation, or in conjunction with each other. Foveal schisis may be... (Review)
Review
Retinoschisis can be found in the fovea or the retinal periphery, either of which may be present in isolation, or in conjunction with each other. Foveal schisis may be congenital, acquired, or secondary to an associated ocular pathology such as optic pit, glaucoma, or pathological myopia. The visual acuity is dependent on the cause of the schisis and appropriate treatment is variable based on likelihood for progression and visual impact. There are many useful considerations and tools for evaluation and monitoring that can be used to determine the aetiology and prognosis of these retinal findings. Retinoschisis is a diagnosis of exclusion, and pathology must be ruled out to accurately make the diagnosis. A review of two cases and following discussion summarises the various types, manifestations, presentations, and complications of retinoschisis and their evaluation, management, and appropriate monitoring or treatment. These cases lead a dialogue on the presentation and aetiology of retinoschisis, important considerations for differential diagnoses, and appropriate management.
Topics: Fovea Centralis; Humans; Retinoschisis; Tomography, Optical Coherence; Visual Acuity
PubMed: 31663163
DOI: 10.1111/cxo.12977 -
BMC Research Notes May 2021Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no...
OBJECTIVE
Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no locus heterogeneity has been reported. However, there are reports showing overlapping features of Norrie disease and retinoschisis in a NDP knock-out mouse model and also the involvement of both the genes in retinoschisis patients. Yet, the exact molecular relationships between the two disorders have still not been understood. The study investigated the association between retinoschisin (RS1) and norrin (NDP) using in vitro and in silico approaches. Specific protein-protein interaction between RS1 and NDP was analyzed in human retina by co-immunoprecipitation assay and MALDI-TOF mass spectrometry. STRING database was used to explore the functional relationship.
RESULT
Co-immunoprecipitation demonstrated lack of a direct interaction between RS1 and NDP and was further substantiated by mass spectrometry. However, STRING revealed a potential indirect functional association between the two proteins. Progressively, our analyses indicate that FZD4 protein interactome via PLIN2 as well as the MAP kinase signaling pathway to be a likely link bridging the functional relationship between retinoschisis and Norrie disease.
Topics: Animals; Blindness; Eye Proteins; Genetic Diseases, X-Linked; Humans; Mice; Mutation; Nervous System Diseases; Retina; Retinal Degeneration; Retinoschisis; Spasms, Infantile
PubMed: 34039417
DOI: 10.1186/s13104-021-05617-5