Month: 01 May 2017
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Pre-clinical research shows re-programming of sugar metabolism may benefit electrophysiology and retinal anatomy in retinitis pigmentosa (RP) models.
Scientists based at the Department of Ophthalmology, Columbia University, New York, have shown that manipulating a metabolic pathway in photoreceptor cells may provide benefit in models of retinitis pigmentosa (RP). While the research is at a significantly early stage, the under-lying principle of re-programming sugar metabolism may provide a potential strategy to impact the course of disease progression, according to the study authors. Animal models treated to alter their photoreceptor metabolism to favour glycolysis showed improved retinal electrophysiology and anatomical structures in their outer segments. According to one of the researchers, Dr. Vinit B. Mahajan, MD, PhD, from the University of Iowa, the experimental approach would not be immediately applicable to humans however, several established enzyme blockers bringing about a similar effect could be evaluated for human clinical testing.
As is well established in the medical literature, RP affects an estimated 1.5 million people globally, with 1 in 10 Americans carrying a recessive RP allele. One such genetic mutation occurs in the phosphodiesterase-6 (PDE6) gene, coding for a G protein effector known to control cGMP levels. This lesion affects rod photoreceptor cells to begin, causing a patient to initially experience poor night vision. As the rod photoreceptors deteriorate, cone photoreceptor cell death follows by means of apoptotic pathways leading to increased visual impairment. An estimated 8% of all recessive RP is understood to arise from mutations in the PDE6 gene. Consequently, to test a clinically relevant model, the researchers used mice with a histidine to glutamine mutation in the Pde6 gene (bH620Q/H620Q), a model of the disease in which a severe form of RP begins approximately 2–3 weeks after birth, resulting in almost complete blindness by the age of 8 weeks. Given that photoreceptors are significantly active cells, converting 80%–96% of glucose into lactic acid via aerobic glycolysis, part of the disease pathology is thought to arise from defective metabolic processes. Based on this assumption, the research team attempted to rescue degeneration by encouraging the photoreceptors to engage in anabolism, (the building up of molecules from smaller units, as opposed to catabolism which breaks down larger molecules). This was achieved by inhibiting Sirt6, a transcriptional histone deacetylase repressor of glycolytic flux. The team used a gene therapy based mechanism to interfere with Sirt6 using an inducible gene disruption strategy.
The effects of the gene disruption was to re-programme rods into a process of perpetual glycolysis in order driving the accumulation of biosynthetic intermediates which could improve outer segment (OS) length and thereby enhance photoreceptor survival and functional vision. Treated models showed an up-regulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis and provided electrophysiological and anatomic rescue of both rod and cone photoreceptors. Commenting on the study, Prof. Stephen H. Tsang, MD, Ph.D., stated that, “although gene therapy has shown promise in RP, it is complicated by the fact that defects in 67 genes have been linked to the disorder, and each genetic defect would require a different therapy. Our study shows that precision metabolic reprogramming can improve the survival and function of affected rods and cones in at least one type of RP. Since many, if not most, forms of the disorder have the same metabolic error, precision reprogramming could conceivably be applied to a wide range of RP patients.”Back to previous