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Molecular Diagnosis & Therapy Jan 2022Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the... (Review)
Review
Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.
Topics: Animals; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Genetic Therapy; Humans; Mutation; Retinal Cone Photoreceptor Cells
PubMed: 34860352
DOI: 10.1007/s40291-021-00565-z -
Handbook of Clinical Neurology 2021Color is a fundamental aspect of normal visual experience. This chapter provides an overview of the role of color in human behavior, a survey of current knowledge... (Review)
Review
Color is a fundamental aspect of normal visual experience. This chapter provides an overview of the role of color in human behavior, a survey of current knowledge regarding the genetic, retinal, and neural mechanisms that enable color vision, and a review of inherited and acquired defects of color vision including a discussion of diagnostic tests.
Topics: Color Vision; Color Vision Defects; Humans; Retina
PubMed: 33832674
DOI: 10.1016/B978-0-12-821377-3.00005-2 -
The Yale Journal of Biology and Medicine Dec 2017Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal... (Review)
Review
Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in , , , , , or . Animal models of , , and have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective.
Topics: Animals; Circadian Rhythm; Clinical Trials as Topic; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Dependovirus; Disease Models, Animal; Dogs; Genetic Therapy; Humans; Mice; Retina
PubMed: 29259520
DOI: No ID Found -
Survey of Ophthalmology 2016Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from... (Review)
Review
Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.
Topics: Color Perception Tests; Color Vision; Color Vision Defects; Humans; Retinal Cone Photoreceptor Cells; Visual Field Tests
PubMed: 26656928
DOI: 10.1016/j.survophthal.2015.11.004 -
EMBO Molecular Medicine Apr 2021Gene therapy using recombinant adeno-associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful...
Gene therapy using recombinant adeno-associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2-based peptide-display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high-level retinal transduction after intravitreal injection in mice, dogs and non-human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof-of-concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone-specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3 mouse model of achromatopsia. These novel rAAV vectors expand the clinical applicability of gene therapy for blinding human retinal dystrophies.
Topics: Animals; Capsid; Color Vision Defects; Dependovirus; Dogs; Genetic Therapy; Genetic Vectors; Mice; Retina
PubMed: 33616280
DOI: 10.15252/emmm.202013392 -
Current Opinion in Ophthalmology Jul 2015The purposes of this article are to examine the literature published on achromatopsia and provide a comprehensive review of the clinical disease, genetic... (Review)
Review
PURPOSE OF REVIEW
The purposes of this article are to examine the literature published on achromatopsia and provide a comprehensive review of the clinical disease, genetic characteristics, and potential for therapy. Specifically, this article will describe recent advances in gene therapy in animal models, clinical features in human, and barriers to human translation.
RECENT FINDINGS
Building on prior success with adeno-associated virus (AAV) therapy in mice models for achromatopsia with mutations in the CNGB3, CNGA3, or GNAT2 genes, multiple cone-specific promoters have recently been developed and shown success in mice and nonhuman primates. A sheep CNGA3 model has also been characterized. Two clinical trials are under way: one to better characterize humans with achromatopsia and another to study a ciliary neurotrophic factor (CNTF) implant as a treatment for patients with the CNGB3 mutation.
SUMMARY
Genetic understanding and disease characterization of achromatopsia continues to evolve, as do gene therapy tools and animal models. The potential for the treatment of achromatopsia in humans with gene therapy shows great promise.
Topics: Animals; Ciliary Neurotrophic Factor; Color Vision Defects; Genetic Therapy; Genetic Vectors; Humans; Mutation
PubMed: 26196097
DOI: 10.1097/ICU.0000000000000189 -
Advances in Experimental Medicine and... 2018Rod monochromatism (achromatopsia) is a congenital cone photoreceptor disorder, which is rare, affecting about 1 in 30,000 individuals. These patients have normal rod... (Review)
Review
Rod monochromatism (achromatopsia) is a congenital cone photoreceptor disorder, which is rare, affecting about 1 in 30,000 individuals. These patients have normal rod function but no detectable cone function; therefore, everything they see is in shades of gray (total color blindness). Patients usually present in infancy with nystagmus and photophobia. Vision is usually about 20/200 or worse; patients have a hyperopic refractive error. Some patients show paradoxical pupillary response; that is, the pupils dilate in bright light. Fundus examination is normal, though pigmentary mottling and atrophic changes may be observed at the macula. Incomplete achromatopsia: Patients in this group have somewhat better visual acuity, about 20/80 to 20/120, with some residual functioning of cone photoreceptors. This milder form allows some color discrimination. Complete achromatopsia: It occurs in about 4-10% of Pingelapese islanders, who live on one of the Eastern Caroline Islands of Micronesia.
Topics: Color Vision Defects; Humans; Nystagmus, Pathologic; Photophobia; Retinal Cone Photoreceptor Cells; Visual Acuity
PubMed: 30578497
DOI: 10.1007/978-3-319-95046-4_24 -
Handbook of Experimental Pharmacology 2017As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations... (Review)
Review
As our understanding of the genetic basis for inherited retinal disease has expanded, gene therapy has advanced into clinical development. When the gene mutations associated with inherited retinal dystrophies were identified, it became possible to create animal models in which individual gene were altered to match the human mutations. The retina of these animals were then characterized to assess whether the mutated genes produced retinal phenotypes characteristic of disease-affected patients. Following the identification of a subpopulation of patients with the affected gene and the development of techniques for the viral gene transduction of retinal cells, it has become possible to deliver a copy of the normal gene into the retinal sites of the mutated genes. When this was performed in animal models of monogenic diseases, at an early stage of retinal degeneration when the affected cells remained viable, successful gene augmentation corrected the structural and functional lesions characteristic of the specific diseases in the areas of the retina that were successfully transduced. These studies provided the essential proof-of-concept needed to advance monogenic gene therapies into clinic development; these therapies include treatments for: Leber's congenital amaurosis type 2, caused by mutations to RPE65, retinoid isomerohydrolase; choroideremia, caused by mutations to REP1, Rab escort protein 1; autosomal recessive Stargardt disease, caused by mutations to ABCA4, the photoreceptor-specific ATP-binding transporter; Usher 1B disease caused by mutations to MYO7A, myosin heavy chain 7; X-linked juvenile retinoschisis caused by mutations to RS1, retinoschisin; autosomal recessive retinitis pigmentosa caused by mutations to MERTK, the proto-oncogene tyrosine-protein kinase MER; Leber's hereditary optic neuropathy caused by mutations to ND4, mitochondrial nicotinamide adenine dinucleotide ubiquinone oxidoreductase (complex I) subunit 4 and achromatopsia, caused by mutations to CNGA3, cyclic nucleotide-gated channel alpha 3 and CNGB3, cyclic nucleotide-gated channel beta 3. This review includes a tabulated summary of treatments for these monogenic retinal dystrophies that have entered into clinical development, as well as a brief summary of the preclinical data that supported their advancement into clinical development.
Topics: Color Vision Defects; Humans; Leber Congenital Amaurosis; Optic Atrophy, Hereditary, Leber; Proto-Oncogene Mas; Retinal Dystrophies; Retinitis Pigmentosa
PubMed: 28035529
DOI: 10.1007/164_2016_91 -
The British Journal of Ophthalmology Jan 2016The cone dysfunction syndromes are a heterogeneous group of inherited, predominantly stationary retinal disorders characterised by reduced central vision and varying... (Review)
Review
The cone dysfunction syndromes are a heterogeneous group of inherited, predominantly stationary retinal disorders characterised by reduced central vision and varying degrees of colour vision abnormalities, nystagmus and photophobia. This review details the following conditions: complete and incomplete achromatopsia, blue-cone monochromatism, oligocone trichromacy, bradyopsia and Bornholm eye disease. We describe the clinical, psychophysical, electrophysiological and imaging findings that are characteristic to each condition in order to aid their accurate diagnosis, as well as highlight some classically held notions about these diseases that have come to be challenged over the recent years. The latest data regarding the genetic aetiology and pathological changes observed in the cone dysfunction syndromes are discussed, and, where relevant, translational avenues of research, including completed and anticipated interventional clinical trials, for some of the diseases described herein will be presented. Finally, we briefly review the current management of these disorders.
Topics: Color Vision Defects; Genotype; Humans; Phenotype; Retinal Cone Photoreceptor Cells; Retinal Diseases; Syndrome
PubMed: 25770143
DOI: 10.1136/bjophthalmol-2014-306505 -
The British Journal of Ophthalmology May 2022Normal foveal development begins at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer... (Review)
Review
Normal foveal development begins at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal lamination of the IRLs sometimes with persistent IRLs. Morphology of FH provides clues to diagnoses, and grading correlates to visual acuity. The outer segment thickness is a surrogate marker for cone density and in foveal hypoplasia this correlates strongly with visual acuity. In preverbal children grading FH can help predict future visual acuity.
Topics: Child; Color Vision Defects; Eye Abnormalities; Fovea Centralis; Humans; Tomography, Optical Coherence; Vision Disorders; Visual Acuity
PubMed: 33148537
DOI: 10.1136/bjophthalmol-2020-316348