Identification of Novel Therapeutics for Danon Disease Using an iPS Model of the Disease

The goal of our project was to use stem cells to help identify new drugs for the treatment of Danon Disease, a rare, inherited disease that causes severe heart disease. Patients with Danon disease generally die in the second and third decade of life of heart failure. We have been working on this project for roughly one year. Since starting we have developed multiple stem cell lines from patients with Danon Disease. We have used these stem cells to make heart cells and have begun testing medicines on these heart cells to see if we can get them to work better. We plan in the future to identify new medicines to test any new medicines we identify on mice that have been made to mimic the disease. We are very hopeful that by the end of this project we will have come up with new ways for helping patients with this deadly disease.

The goal of our project is use stem cells to help identify new drugs for the treatment of Danon Disease, a rare, inherited disease that causes severe heart disease. Patients with Danon disease generally die in the second and third decade of life of heart failure. We have been working on this project for roughly two yeara. Since starting we have developed over 7 stem cell lines from patients with Danon Disease. We have used these stem cells to make heart cells and have screened hundreds of drugs on these cells. We have identified several drugs using this system that show some promise and are undergoing more rigorous testing. We have also begun working with mice that have been genetically engineered to model Danon disease. We hope that these mice can be used to test out the new drugs we have identified using our stem cell screens.

The broad objective of this project is the identification of new medicines for the treatment of Danon disease using a cell-based screening system. To achieve this goal, we use cells derived from stem cells from patients with Danon disease to identify potential medicines. Potential medicines identified in the screen will then be tested on heart cells to confirm that they improve cardiomyocyte function. We will then optimize and generate large quantities of the leading medicines identified through these screens and test them on mice. Our strategy is based on previously established findings in our lab that Danon stem cell derived heart cells retain key features of the patients from which they were derived. Using cells generated from Danon disease patients, we have confirmed that these cells have impaired function. Initially we plan to screen FDA-approved compounds using this system and then move onto pathway-based small molecule libraries if no FDA-approved compounds are identified. The most promising compounds identified in these screens will then be tested in an established mouse model of Danon disease. We continue to make progress toward these goals. Currently, we have performed two separate small molecule screens from which we have identified >10 potential compounds of interest. Furthermore, based on pathway analysis done in fibroblasts we have identified one FDA-approved compound for testing in our mouse model.

The goal of our research project is to develop new therapies to treat Danon disease, a life threatening disorder that causes heart failure. During this reporting period we evaluated a number of potential therapies to treat the disease. We used cells to evaluate the therapies and then used a mouse that has been altered to mimic Danon disease. Some of the results are promising and may lead to future studies to develop new treatments.