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Exploring the pathophysiology and treatment of LCHADD retinopathy

探索 LCHADD 视网膜病变的病理生理学和治疗

基本信息

批准号：
10470841
负责人：
Melanie B Gillingham
金额：
$ 37.35万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10470841
关键词：
3-Hydroxyacyl-CoA dehydrogenase Address Animals Blindness Blood CRISPR/Cas technology Cell Culture Techniques Cell Differentiation process Cells Cessation of life Child Childhood Chronic Coculture Techniques Color Visions Complication Defect Deterioration Development Diet therapy Disease Early Diagnosis Early Intervention Early treatment Electroretinography Exhibits Experimental Models Fatty Acids Fibroblasts Functional disorder Future Gene Transfer Genes Genetic Goals Hepatic Hydrogen Peroxide Impairment In Vitro Ketones Knock-in Light Lipids Liver Mediating Metabolic Mitochondria Modality Modeling Molecular Mus Muscle Mutation Natural History Neonatal Screening Organ Outcome Oxidative Stress Oxides Oxidoreductase Palmitates Pathologic Pathology Patients Peripheral Phenotype Photoreceptors Pigments Plasma Point Mutation Predisposition Production Protein Deficiency Recombinant adeno-associated virus (rAAV)Retina Retinal Degeneration Retinal Diseases Retinal Pigments Retinal gene therapy Role Series Structure Structure of retinal pigment epithelium Testing Time Toxic effect Toxin Vision Visual Acuity Wild Type Mouse acylcarnitine adeno-associated viral vector cell type design experimental study fatty acid oxidation gene therapy human disease in vitro Model induced pluripotent stem cell macula mouse model mutant mouse model novel novel therapeutics oxidation oxidative damage preservation prevent response restoration retinal damage visual performance

项目摘要

Project Summary Progressive retinopathy with vision loss is a unique complication of Long-chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) and mitochondrial Trifunctional Protein Deficiency (TFPD), rare genetic fatty acid oxidation (FAO) disorders. Gradual macular pigment clumping, followed by progressive deterioration of the retina occurs in almost all LCHADD patients beginning in childhood and progressing over time. This manifests initially as decreased night vision, progresses to loss of color vision, and ultimately to decreased central vision. While early diagnosis through newborn screening and sustained dietary therapy can slow progression, no successful treatment directed at retinopathy currently exists, and children with LCHADD/TFPD continue to suffer progressive blindness. Novel treatments for LCHADD-associated retinopathy are needed but appropriate experimental models have been lacking. We recently created 2 models of LCHADD-retinopathy; a murine knockin of c.1528G>C, the common mutation in the HADHA gene that causes LCHADD, and cultured RPE-like cells differentiated from induced pluripotent stem cells (iPSC) derived from patients' fibroblasts. The pathophysiology of LCHADD-associated retinopathy is not completely understood but begins with loss of retinal pigment epithelium (RPE). Two potential molecular mechanisms include; energy deficit due to decreased FAO to support normal RPE functions, or selective toxicity of accumulating partially oxidized fatty acid metabolites. Children with lower blood concentrations of LCHADD-specific 3-hydroxy-acylcarnitines have preserved retinal function implying that retinal damage may be mediated through accumulation of toxic fatty acid intermediates. If so, then gene therapy directed toward a peripheral organ such as muscle or liver could lower circulating toxic metabolites, prevent retinal degeneration, and address other LCHADD-associated complications. Alternatively, retinal preservation may require the restoration of LCHAD activity directly in RPE, and circulating acylcarnitines are simply a marker of partial FAO in the retina. We will use our 2 models of LCHADD-retinopathy to test which approach will prevent RPE dysfunction and retinal degeneration. LCHADD-RPE exhibit decreased ability to oxidize palmitate, accumulated acylcarnitines and neutral lipids, and increased susceptibility to H2O2 oxidative stress in comparison to wild type (WT) RPE. We propose a series of experiments to test LCHADD-associated RPE alterations such as lipid processing and sensitivity to H2O2 treatment under different FAO conditions compared to WT RPE. Additionally, the LCHADD-mouse has decreased visual performance and electroretinogram (ERG) responses compared to WT mice. Our goal is to characterize the visual acuity, retinal structure and function of LCHADD mice and to test the effects of hepatic versus retinal directed gene therapy approaches. The outcome of these experiments will expand our understanding of LCHAD-specific pathology and provide the basis for a translational effort to treat LCHADD retinopathy, potentially with retinal gene therapy, a new treatment modality of which OHSU is a national leader.

项目总结