Lowe Syndrome: Therapeutic Strategy by Drug Repositioning

点击翻译按钮获取中文摘要

Lowe Syndrome (LS) is a lethal genetic disease described in the early fifties; however, no specific treatment against this devastating condition is available to affected children. However, this project aims to change that unfortunate situation. Specifically, we recently found that LS abnormalities can be reversed by repositioning two FDA-approved drugs currently used for other indications. Our lab previously established that LS patient cells exhibit two phenotype categories: RhoGTPase signaling abnormalities and primary cilia assembly defects. Therefore, using LS patient cells, we tested FDA- approved drugs for their ability to revert these phenotypes and identified two medicine groups as suppressors of LS patient abnormalities. However, the impact that different OCRL1 patient mutations have on the penetrance of each phenotype category and on the drug response is still unknown. Here we hypothesize that different OCRL1 patient mutations have differential impact on Ocrl1 biochemical activities and in consequence lead to diverse phenotype category penetrance and sensitivity to anti-LS drugs. This project’s goal is to test this hypothesis and the ability of the compounds to revert phenotypes associated with renal failure in kidney cells in vivo and in vitro. We will pursue the following specific aims: Aim 1. To determine the effect of different OCRL1 patient mutations on LS phenotype category severity and on candidate drug-mediated phenotype suppression. Aim 2. To determine the impact of different OCRL1 patient mutations on Ocrl1 biochemical activity. Aim 3. To test different drug therapy schemes for suppression of renal abnormalities in a LS animal model. This project has high significance as it will produce a novel LS theoretical framework and it will address the lack of therapeutic approaches designed to suppress the causes of LS. Importantly, the candidate drugs are currently used in children to ameliorate other conditions and can be readily repurposed to LS (i.e., known safety and low risk of adverse toxicology). Therefore, the translational potential and impact of this project is very high. Further, since our investigations unveiled that LS shares some characteristics with other genetic diseases such as ciliopathies, these discoveries may also impact patients suffering other conditions besides LS.