Therapies for Mitochondrial Diseases
Identifying targets and screening compounds that inhibit the mTOR pathway using a mouse model and patient cell lines
Mitochondrial diseases have diverse causes. They can result from mutations in either the nuclear or mitochondrial genomes. For example, mutations in nuclear or mitochondrial genes can lead to Leigh syndrome, but all patients with this disease have characteristic central nervous system lesions and impaired mitochondrial function. Leigh syndrome is usually fatal within the first 10 years of life.
Rapamycin for mitochondrial diseases
Simon Johnson published a study in 2013 showing that rapamycin prevents the brain lesions and greatly extends survival in a mouse model of Leigh syndrome. Ndufs4 knockout mice are the premier model for studying development and treatment of Leigh syndrome because the mice have the same brain lesions and mitochondrial defects as humans with the disease. Rapamycin is a specific inhibitor of the mTOR (mechanistic target of rapamycin) signaling pathway. The drug is an immunosuppressant and a cancer therapy, among other uses.
Dr. Johnson is now expanding this work. His group continues to use Ndufs4 mice to study the development of Leigh syndrome and mechanisms that might yield drug targets. In particular, the Johnson laboratory is screening pathways up- and down-stream of mTOR in search of better therapeutic targets in this pathway.
The Johnson lab is also investigating mTOR inhibition for other diseases such as the MELAS group (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) of mitochondrial conditions. Recent results support that mTOR inhibition is broadly beneficial for many distinct forms of mitochondrial disease.
These findings could translate to large effects. Although each mitochondrial disease is rare, collectively, they are estimated to occur at a rate greater than 1 in 4000 live births in the United States. In addition, many forms of age-related disease involve mitochondrial dysfunction and may benefit from the same therapeutic solutions as pediatric genetic mitochondrial disorders.
Patient cell models and new mTOR targets
The Johnson group developed methods to use primary fibroblast cells from patients with a variety of mitochondrial diseases to investigate how mTOR inhibition alleviates the effects of these diseases and prolongs survival.
To avoid rapamycin limitations such as poor bioavailability and effects on growth, they are using patient cells to identify additional drug targets in the pathway such as kinases upstream or downstream of mTOR.
Dr. Johnson is interested in partnerships, including for assay development and optimization, to test drugs targeting the mTOR and related signaling pathways for mitochondrial diseases.
Stage of Development
- Pre-clinical in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Johnson SC, Martinez F, Bitto A, Gonzalez B, Tazaerslan C, Cohen C...et al. mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. Kidney Int. 2019;95(2):455-466.
- Johnson SC, Yanos ME, Bitto A, Castanza A, Gagnidze A, Gonzalez B, Gupta K...et al. Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice. Front Genet. 2015. 22;6:247.
- Johnson SC. Translational Medicine. A target for pharmacological intervention in an untreatable human disease. Science. 2014;346(6214):1192.
- Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L...et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013;342(6165):1524-8.
- Schleit J, Johnson SC, Bennett CF, Simko M, Trongtham N, Castanza A, Hsieh EJ...et al. Molecular mechanisms underlying genotype-dependent responses to dietary restriction. Aging Cell. 2013;12(6):1050-61.