Bioenergetic Rescue of Mitochondrial Disease Mutations
Abstract
The Fiscal Year 2016 Peer Reviewed Medical Research topic area this proposal addresses is Mitochondrial Diseases. The central problem that is addressed in this application is to find genes encoding for proteins that can be used in targeted therapy to treat mitochondrial (the main powerhouse of the cell, responsible for energy generation) disease patients. Mitochondrial diseases represent a very diverse group of diseases that are very severe and largely affect children, but adult onset is becoming more and more common. Clinically, based on the severity of the tissues affected, the symptoms are muscle weakness and pain, loss of motor control, heart and liver diseases, seizures, visual/hearing problems, developmental problems, and elevated risk of infection. At this time, there are no cures for mitochondrial diseases. Treatments are more often palliative and mainly include vitamin cofactors, nutritional manipulations, and exercise. Currently, many potential therapeutic agents are focused on treating the symptoms rather than correcting the defect itself and to slow down the progression of the disease. The effectiveness of the therapy varies and depends on the mitochondrial disorder and treatment for each patient needs to be tailored to a specific treatment that is very often empiric. The key points of treatment are focused on standard therapies for known symptoms, for example, physical therapy for motor problems, nutrition, and avoidance of stressful factors including fasting, and cold or heat stresses. These stresses are highly relevant to the military personnel in training or combat and exacerbate the symptoms of mitochondrial disorders. Mitochondrial diseases result from mutations (errors or defects) in mitochondrial or nuclear (part of a cell) DNA that cause failures in energetic function. Therefore, different treatments, drugs or medications that provide rescue of this energetic deficit can be considered potential therapies. In this context, this application proposes a series of innovative studies to discover genes encoding for proteins that can be targeted to cure these mitochondrial defects with the same errors that are found in mitochondrial disease patients. Targeting these proteins will rescue the energetic defects and will maintain healthy and functional mitochondria. In mice, for example, activation of mitochondrial energetic activities strongly ameliorates the clinical symptoms developed by defects similar to mitochondrial disease patients. The research strategy in this application proposes a series of innovative technologies that will allow discovery of new genes that could be targeted to treat mitochondrial diseases. The ultimate applicability of the research proposed in this application is that the discovery of novel genes will allow one to find drugs that, once validated in humans and clinical trials, could be used to treat patients with mitochondrial diseases. In addition, since mitochondrial disorders are also encountered in other diseases including neurodegeneration, the findings of this application might also be applicable to other human diseases. As a consequence, the overall impact of the research presented and developed in this application is very high and might represent new clinical avenues to treat patients with mitochondrial disorders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710216
Entities
People
- Pere Puigserver i Burguera
Organizations
- Dana–Farber Cancer Institute
- United States Army