Metformin Explored as a Treatment for L-ORD

Article: NIH study traces molecular link from gene to late-onset retinal degeneration
Source: National Eye Institute
Published: December 9, 2021 
Article: LSU Health Contributes to Research Suggesting Late-Onset Retinal Degeneration Mechanism & Potential Rx
Source: Louisiana State University
Published: December 9, 2021

Metformin counteracts the increased susceptibility to dedifferentiation in L-ORD-iRPE

Late-onset retinal degeneration (L-ORD) is a rare genetic disorder of autosomal dominant inheritance. Specifically, L-ORD is caused by a missense substitution in the gene that encodes the protein CTRP5, leading to choroidal neovascularization and deposits of apolipoprotein E (which is involved in lipid metabolism within the retina), and retinal pigmented epithelium (RPE) atrophy (which contain an abundance of fatty acids and lipids). Symptoms begin with nyctalopia, progressing to central vision loss by the sixth decade. Scientists at the National Eye Institute are studying the disease by developing a "disease-in-a-dish" model from induced pluripotent stem cells (iPSCs) to make RPE cells from skin fibroblasts; the fibroblast samples were collected from two siblings with L-ORD (L-ORD-iRPE) and compared with two unaffected siblings who lacked the disease-causing mutation. The L-ORD-iRPE were observed to be dysmorphic (deformed), also showing deposits of apolipoprotein E near the tissue and abnormal secretions of vascular endothelial growth factor (VEGF); these cells also had reduced secretions of both normal and mutant CTRP5 proteins.

Computer modeling of the proteins showed that mutant CTRP5 was less likely to bind with cell receptors that regulate lipid metabolism, in turn leading to chronic activation of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis and lipid metabolism, such as of apolipoprotein E. One of the researchers explains, "AMPK in the RPE itself is a key regulator of the conversion of DHA [docosahexaenoic acid] into protective mediators [against oxidative damage and mutations]." Chemically inhibited AMPK in the L-ORD-iRPE cells led to fewer apolipoprotein E deposits and less abnormal secretion of VEGF. Finally, the researchers tested two therapies on the L-ORD-iRPE cells: a gene augmentation of normal CTRP5, and modulation of AMPK with anti-diabetes drug metformin. Both strategies prevented signs of L-ORD in the RPE model. Senior author of the study states, "Importantly, we now have two potential strategies to disrupt the L-ORD disease process. While gene therapy may be years away, metformin is a drug that’s long been used to treat diabetes." Although L-ORD is a rare genetic disease, it shares some characteristics with the much more common age-related macular degeneration (AMD). The researchers hope that studying this model, and the effect of metformin, will benefit diseases caused by RPE changes.

My rating of this study: ⭐⭐⭐

Miyagishima KJ, Sharma R, Nimmagadda M, et al. "AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration." Communications Biology.  4:1360. 9 December 2021. https://doi.org/10.1038/s42003-021-02872-x