Therapies for Mitochondrial Diseases

Identifying pathways, targets, and new interventions for treating childhood mitochondrial disorders and related seizures

Technological overview

Pediatric mitochondrial diseases such as Leigh, Alpers, and Rett syndromes are caused by mutations in the nuclear or mitochondrial genomes. Children with these genetic disorders often have severe neuromuscular and neurological symptoms including seizures, which affect up to 60% of children with a mitochondrial disease. These seizures often do not respond to antiepileptic therapies, indicating they may arise from pathways and mechanisms unique to mitochondrial disorders.

Dr. Simon Johnson

Dr. Johnson uses specialized animal models to investigate the underlying causes of the seizures and other pathologies associated with mitochondrial diseases. His goal is to identify pathways and pathway components that are promising targets for drugs and other therapeutic strategies for children with mitochondrial diseases.

Examples of models used by the Johnson group include Ndufs4 knockout mice, which are the premier model for studying development and treatment of Leigh syndrome. Dr. Johnson used these mice to show that rapamycin, a drug used as an immunosuppressant and a cancer therapy, has therapeutic effects in the Ndufs4 mice. Dr. Johnson also works with the harlequin mouse model, which carries a defect in Aifm1, a mitochondria-associated apoptosis factor. Through collaborative work, the lab is involved in state-of-the-art methods for developing and working with knock-in mice that carry mutations found in patients with mitochondrial diseases.

Examples of mechanistic investigations by the Johnson group include studying how inhibition of mTOR, a key cellular nutrient sensing factor and low oxygen (hypoxia) alleviate disease in mouse models of mitochondrial syndromes. The Johnson lab is also examining how a ketogenic diet reduces seizures in children with mitochondrial diseases. Identifying the precise mechanisms and pathways of these interventions will identify new druggable targets and indicate if existing pharmacological agents in metabolism and hypoxia sensing and response could be effective for mitochondrial disorders.

The Johnson group has experience using animal models to screen small compounds for therapeutic effects. For example, using Ndufs4 mice, they developed a catalog of agents that target a specific pathway of neural inflammation initiated by the Csf1 receptor. Other components of this pathway include substrates of phosphoinositide 3-kinases (PI3Ks), including targets of existing PI3K inhibitors. The Johnson lab is testing these agents in other models of neural inflammation for their potential to treat mitochondrial diseases.

Dr. Johnson’s findings could translate to large effects. Although each mitochondrial disease is rare, they are collectively estimated to occur at more than 1 in 4000 U.S. live births. In addition, many forms of age-related disease involve mitochondrial dysfunction and may benefit from the same therapeutic solutions as pediatric mitochondrial disorders. Dr. Johnson is interested in partnerships to identify and test drugs targeting pathways involved in mitochondrial diseases. 

Stage of Development

• Pre-clinical in vivo

Partnering Opportunities

• Collaborative research opportunity
• Sponsored research agreement
• Consultation agreement

Publications

1. 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.
2. 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.
3. Johnson SC. Translational Medicine. A target for pharmacological intervention in an untreatable human disease. Science. 2014;346(6214):1192.
4. 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.
5. 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.

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