Loss of RPE leads to the death of photoreceptors and in turn, to loss of vision. Led by Kapil Bharti, Ph. Importantly, the findings shed light on how genetic variants affect AMD development. Previous genetic studies had shown that some AMD patients have variants in genes responsible for regulating the alternate complement pathway, a key part of the immune system. However, it was unclear how the genetic variants led to disease.
One hypothesis was that patients with such variants lacked the ability to regulate the alternate complement pathway once it had become activated, resulting in the formation of anaphylatoxins, a type of protein that mediates inflammation, among other biological functions. To test this hypothesis, the researchers exposed 10 iPSC-derived RPE cell lines involving different genetic variants to anaphylatoxins from human serum.
They predicted that such a stress challenge would act as a surrogate for age-induced increases in alternate complement pathway that had been observed in the eyes of patients with AMD.
While signs of disease progression occurred among all 10 types of iPSC-derived RPE cells used in the study, they were worse in the iPSC-derived RPE from patients with high-risk variants in the alternate complement pathway, compared to those with low-risk variants, which gave the researchers a way to discern specific effects of genotype on disease characteristics. Using the model, they screened more than 1, drugs from a library of pharmacological agents that had been tested for a range of other conditions.
The screen flagged two drugs for their ability to inhibit RPE atrophy and drusen formation: A protease inhibitor called aminocaproic acid, which likely directly blocks the complement pathway outside cells and a second agent L , which stops complement induced inflammation inside the cell indirectly via inactivation of the dopamine pathway. Have a news tip, correction or comment? Email catarina. Thank Reply 1 Share. The rules of replying: Be respectful. This is a space for friendly local discussions.
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