Autophagy is the cells mechanism for breaking down and recycling proteins. Danon disease is an inherited disorder of autophagy. Patients with this disease have major abnormalities in heart and skeletal muscle and generally die by the time they are in their 20s. Recently we used a new technology to turn skin cells from two patients with this disease into stem cells. The objective of our work is to use these cells to find new medications. To achieve this objective we will use techniques we helped develop to make Danon disease stem cells into heart cells. We will then screen hundreds of thousands of different drugs on these heart cells, to find drugs that make these cells work better. The most promising drugs will be tested on mice with a genetic defect that is similar to those found in patients with Danon disease. When complete, the proposed research will result in the development of a drug suitable for clinical trials of patients with Danon disease. As impaired autophagy is associated with may other diseases, including heart failure, cancer and Parkinson's disease, it is possible that the drug identified will be suitable for treatment of a variety of ailments. Furthermore, the studies will serve as proof of concept for other stem cell based drug discovery systems.
Heart failure is among the most common reasons Californians are hospitalized, and one of the greatest expenses for the health care system. Danon disease is a type of heart failure that patients inherit. It is rare but almost always fatal. Patients who suffer from Danon disease cannot correctly perform autophagy, which is a way that cells recycle proteins. We believe that our work will help in the development of new drugs to treat Danon disease. It is also possible that the drugs we discover will be useful for the treatment of other types of heart failure. As other disease such as cancer and Parkinson's disease are associated with impaired autophagy, these drugs may help them as well. From a public health perspective, the development of new drugs for heart failure would be of great benefit to Californians. Furthermore, the work could lead to additional grants from federal agency's, as well as larger studies on patients done in partnership with industry. Such studies have the potential of creating jobs and revenue for the state.
This Development Candidate Feasibility (DCF) award application proposes to use patient-derived induced pluripotent cell (iPSC)-based disease models to identify novel therapeutics for Danon disease. Danon disease is an inherited disorder that results in muscle weakness and heart failure. Cells from Danon patients also display defects in autophagy, the normal cellular process of breaking down and recycling proteins. The applicant will develop both high throughput screening and secondary gene expression-based autophagy assays. Using the screen, small molecules will be identified that improve autophagy in patient hiPSC, and these candidates will be tested for their ability to alter cellular function in patient hiPSC-derived cardiomyocytes. Small molecules displaying the desired properties will be optimized and proof-of-concept studies will be completed in a small animal model of Danon disease.
Objectives and Milestones
-The application’s objective to identify candidate therapeutics for Danon disease is appropriate for a DCF award.
-Reviewers found the milestones logical, appropriately designed and well reasoned. Success criteria provided scientifically and clinically meaningful measures to assess milestone achievement. However, the panel cautioned the proposed in vivo testing may not be a realistic goal for this DCF project.
-Reviewers found the Target Product Profile to be appropriate, but noted it would benefit from further development.
Rationale and Significance
-Reviewers found the rationale to target the observed autophagy defect in Danon disease logical and highlighted the lack of available treatments for this disease. However, the panel noted the pathogenic role of autophagy in Danon disease remains to be confirmed.
-The application of iPSC-based disease modeling to Danon disease is a novel approach and could lead to the development of new therapies for this disorder.
-The panel expressed some doubts that successful compounds identified in this program could be universally applied to other autophagy disorders, as Dannon disease appears to display a distinct autophagy phenotype.
Research Project Feasibility and Design
-Overall, the research plan is well designed and focused to achieve the milestones and the project objective.
-Reviewers found the preliminary data impressive and supportive of the proposed research. The panel expressed a desire that the Principal Investigator (PI) profile additional patient cell lines.
-The uncertainty regarding the pathogenic role of autophagy in Danon disease and the interdependence of the aims impart some risk to the program. This was deemed appropriate for a DCF proposal and did not lessen reviewer enthusiasm.
Qualification of the PI and Research Team
-The PI is well trained and well suited to oversee every aspect of this project.
-The research team is a key strength of the proposal and includes well-recognized leaders in stem cell biology, genetics, drug development, and cardiovascular biology.
-The application includes a team communication plan.
Collaborations, Assets, Resources and Environment
-Collaborations are a major strength of this application.
-The institutional and scientific environments are outstanding.
-Although the research is multi-institutional, all centers are within close proximity, which maximizes interactions between the team members.
Responsiveness to the RFA
-The project is responsive to the RFA; no relevant concerns were highlighted under this review criterion.