RESUMEN
RPE65 isomerase, expressed in the retinal pigmented epithelium (RPE), is an enzymatic component of the retinoid cycle, converting all-trans retinyl ester into 11-cis retinol, and it is essential for vision, because it replenishes the photon capturing 11-cis retinal. To date, almost 200 loss-of-function mutations have been identified within the RPE65 gene causing inherited retinal dystrophies, most notably Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (arRP), which are both severe and early onset disease entities. We previously reported a mutation, D477G, co-segregating with the disease in a late-onset form of autosomal dominant RP (adRP) with choroidal involvement; uniquely, it is the only RPE65 variant to be described with a dominant component. Families or individuals with this variant have been encountered in five countries, and a number of subsequent studies have been reported in which the molecular biological and physiological properties of the variant have been studied in further detail, including observations of possible novel functions in addition to reduced RPE65 enzymatic activity. With regard to the latter, a human phase 1b proof-of-concept study has recently been reported in which aspects of remaining vision were improved for up to one year in four of five patients with advanced disease receiving a single one-week oral dose of 9-cis retinaldehyde, which is the first report showing efficacy and safety of an oral therapy for a dominant form of RP. Here, we review data accrued from published studies investigating molecular mechanisms of this unique variant and include hitherto unpublished material on the clinical spectrum of disease encountered in patients with the D477G variant, which, in many cases bears striking similarities to choroideremia.
Asunto(s)
Sustitución de Aminoácidos , Genes Dominantes , Mutación Missense , Mutación Puntual , Retinitis Pigmentosa/genética , cis-trans-Isomerasas/genética , Edad de Inicio , Animales , Coroideremia , Ensayos Clínicos Fase I como Asunto , ADN Complementario/administración & dosificación , ADN Complementario/genética , Terapia de Reemplazo Enzimático , Femenino , Técnicas de Sustitución del Gen , Terapia Genética , Vectores Genéticos/uso terapéutico , Humanos , Amaurosis Congénita de Leber/enzimología , Amaurosis Congénita de Leber/genética , Masculino , Ratones , Linaje , Prueba de Estudio Conceptual , Isoformas de Proteínas/genética , Retinaldehído/uso terapéutico , Retinitis Pigmentosa/diagnóstico por imagen , Retinitis Pigmentosa/enzimología , Retinitis Pigmentosa/terapia , cis-trans-Isomerasas/deficiencia , cis-trans-Isomerasas/fisiología , cis-trans-Isomerasas/uso terapéuticoRESUMEN
Novel therapeutics for inherited retinal dystrophies (IRDs) have rapidly evolved since groundbreaking clinical trials for LCA due to RPE65 mutations led to the first FDA-approved in vivo gene therapy. Since then, advancements in viral vectors have led to more efficient AAV transduction and developed other viral vectors for gene augmentation therapy of large gene targets. Furthermore, significant developments in gene editing and RNA modulation technologies have introduced novel capabilities for treatment of autosomal dominant diseases, intronic mutations, and/or large genes otherwise unable to be treated with current viral vectors. We highlight strategies currently being evaluated in gene therapy clinical trials and promising preclinical developments for IRDs.
Asunto(s)
Edición Génica , Terapia Genética , Distrofias Retinianas/terapia , cis-trans-Isomerasas/genética , Vectores Genéticos/genética , Vectores Genéticos/uso terapéutico , Humanos , Mutación/genética , Distrofias Retinianas/genética , Distrofias Retinianas/patología , cis-trans-Isomerasas/uso terapéuticoRESUMEN
This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
Asunto(s)
Aprobación de Drogas , Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Benzoatos/uso terapéutico , Benzodioxoles/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Combinación de Medicamentos , Péptidos Similares al Glucagón/uso terapéutico , Humanos , Indoles/uso terapéutico , Quinolonas/uso terapéutico , Estados Unidos , United States Food and Drug Administration , beta-Alanina/análogos & derivados , beta-Alanina/uso terapéutico , cis-trans-Isomerasas/uso terapéuticoRESUMEN
Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene-based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies.
Asunto(s)
Pruebas Genéticas , Patología Molecular , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Heterogeneidad Genética , Terapia Genética , Humanos , Fenotipo , Distrofias Retinianas/terapia , cis-trans-Isomerasas/genética , cis-trans-Isomerasas/uso terapéuticoRESUMEN
Leber congenital amaurosis (LCA) is one of the most severe forms of inherited retinal degeneration and can be caused by mutations in at least 15 different genes. To clarify the proteomic differences in LCA eyes, a cohort of retinal degeneration 12 (rd12) mice, an LCA2 model caused by a mutation in the RPE65 gene, were injected subretinally with an AAV vector (scAAV5-smCBA-hRPE65) in one eye, while the contralateral eye served as a control. Proteomics were compared between untreated rd12 and normal control retinas on P14 and P21, and among treated and untreated rd12 retinas and control retinas on P42. Gene therapy in rd12 mice restored retinal function in treated eyes, which was demonstrated by electroretinography (ERG). Proteomic analysis successfully identified 39 proteins expressed differently among the 3 groups. The expression of 3 proteins involved in regulation of apoptosis and neuroptotection (alpha A crystallin, heat shock protein 70 and peroxiredoxin 6) were investigated further. Immunofluorescence, Western blot and real-time PCR confirmed the quantitative changes in their expression. Furthermore, cell culture studies suggested that peroxiredoxin 6 could act in an antioxidant role in rd12 mice. Our findings support the feasibility of gene therapy in LCA2 patients and support a role for alpha A crystallin, heat shock protein 70 and peroxiredoxin 6 in the pathogenetic mechanisms involved in LCA2 disease process.