Exploring the pathophysiology and treatment of LCHADD retinopathy

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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.