Metformin Attenuates the Hallmarks of Stargardt Disease

Abstract

Purpose : Recessive Stargardt disease (STGD1), caused by ABCA4 mutations, is one of the most prevalent causes of macular degeneration in youth, with an onset between the ages of 7 and 12 and no current treatment. Early stages of Stargardt disease are characterized by the buildup of lipid-rich lipofuscin deposits in the retinal pigment epithelium (RPE). We recently showed that ABCA4 loss of function in STGD1-iRPE leads to a cell-autonomous disease phenotype characterized by intracellular lipid accumulation and impaired POS digestion. These defects suggested a potential therapeutic mechanism for STGD1 disease via lipid-lowering drugs. Metformin is an FDA-approved treatment for type 2 diabetes that is known to enhance cellular lipid metabolism by activating the AMPK pathway. To translate metformin as a viable treatment for Stargardt disease, we used Abca4^-/- mouse model known to recapitulate Stargardt retinopathy characteristics, including lipid-rich sub-RPE deposits. We proposed to test the therapeutic effect of metformin in Stargardt patients in the phase I/II trial.

Methods :
Mice were given oral metformin doses of 400 mg/kg/day in drinking water for 8 months, comparable to the human dose. Lipofuscin accumulation was tracked using fundus autofluorescence imaging (FAF) in vivo. Retina and RPE/choroid samples were extracted for lipid analysis from 11-month-old wild-type (C57BL/6J) and Abca4^-/- mice. Additionally, using our in vitro Stargardt disease model, iRPE cells were treated for 7 days with 3mM metformin and POS with 3mM metformin for 10 days. Lipid extracts were subjected to LC-MS/MS for lipidomic analysis.

Results : Mass-spectrometry analysis of the eyes collected from treated animals confirmed the delivery of metformin to the target tissues. FAF analysis showed reduced lipofuscin accumulation in the experimental group. LC-MS/MS analysis of cholesterol metabolites, A2E, and ceramide showed increased accumulation of these metabolites in the retina and RPE/Choroid collected from Abca4^-/- mice, which was drastically reduced by metformin treatment. Similarly, metformin reduced lipid accumulation in Abca4^-/- RPE/Choroid and STGD1-iRPE.

Conclusions : Our findings imply that metformin may be an effective treatment for Stargardt disease. Furthermore, our study shows treatments targeting lipid handling defects can be evaluated for their potential to slow the progression of Stargardt disease.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.