Stem-Cell RPE Model & Two AMD Drug Candidates

Article: NIH researchers identify potential AMD drugs with stem-cell based research tool
Source: National Eye Institute
Published: December 15, 2021 

L-745 and ACA (second and third columns) restore epithelial phenotype
in complement competent human serum (CC-HS)-treated CFH(Y/Y)-iRPE
and CFH(H/H)-iRPE (low- and high-risk AMD alleles, respectively)
compared to vehicle (fourth column)

Researchers at the National Eye Institute developed a stem cell-based model of the eye's retinal pigmented epithelium (RPE) to test therapies for age-related macular degeneration (AMD). In particular, they used fibroblasts (skin cells) or blood samples from AMD patients to produce induced pluripotent stem cells (iPSC), which were in turn programmed to become RPE cells. Using this iPSC RPE model, the researchers tested genetic contributors to AMD development. For example, they tested the hypothesis that AMD is the result of the inability to regulate the alternate complement pathway once it had become activated, resulting in the formation of anaphylatoxins, a protein that mediates inflammation, among other functions. They exposed 10 iPSC-derived RPE cell lines of different genetic variants to anaphylatoxins from human serum, and subsequently observed that these iPSC-derived RPE cells developed drusen deposits and RPE atrophy, two key characteristics of AMD. Furthermore, cell lines from patients with high-risk variants in the alternate complement pathway had worse disease phenotype compared to cell lines from patients with low-risk variants, allowing the researchers to examine the effects of variations in genotype. Secondly, the scientists used the RPE models to screen more than 1,200 drugs from a pharmacologic library of drugs that had been tested for other conditions, which uncovered two candidate drugs that inhibit RPE atrophy and drusen formation: aminocaproic acid (ACA), a protease inhibitor that blocks the complement pathway outside of cells, and L745, a dopamine receptor antagonist that stops complement-induced inflammation indirectly inside the cell by inhibiting the dopamine pathway. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. The scientists hope that the stem cell-based RPE model they developed will be helpful to the research community.

My rating of this study: ⭐⭐⭐

Sharma R, George A, Nimmagadda M, et al. "Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model." Nature Communications.  12:7293. 15 December 2021. https://doi.org/10.1038/s41467-021-27488-x