That treatment led to sustained improvements in a 2-year-old girl with Leigh syndrome, restoring her ability to walk and lessening the effects of brain damage. On the contrary, a 6-year-old boy with MELAS syndrome failed to respond to the therapy, and eventually died of the progressive rare disease.
The study, “Exploring mTOR inhibition as treatment for mitochondrial disease,” was published in the journal Annals of Clinical and Translational Neurology.
Both are severe, disabling encephalopathies that impair the functioning of the central nervous system, the brain and the spinal cord. No effective treatments are available.
Preclinical (in the lab) studies suggest that a potential target to ease disease progression is the mTOR (mammalian target of rapamycin) pathway, a biological route fundamental for regulating cells’ metabolism and physiology.
In mice models of Leigh syndrome, treatment with rapamycin, an mTOR inhibitor, extends lifespan and lessens the progression and severity of the disease.
Similarly, mTOR inhibitors appeared to yield clinical improvements in kidney transplant recipients who had MELAS. Using skin cells collected from these patients, researchers demonstrated that rapamycin rescued the shape, membrane properties, and growth ability of mitochondria — which are the cell structures impaired in people with these type of diseases. Data also suggested decreased muscle protein breakdown, and lower oxidative stress.
Based on these observations, researchers at Columbia University Irving Medical Center were encouraged to investigate the use of a cousin molecule of rapamycin, called everolimus (brand name Zortress, Afinitor, and others), as a possible treatment for children with Leigh syndrome and MELAS.
Everolimus lowers the immune system’s responses in the body. It currently is approved in the U.S. for preventing organ rejection, and for the treatment of certain types of cancer. The medicine is better tolerated than rapamycin, which can lead to a range of side effects, including impaired wound healing, immunosuppression, and hyperlipidemia (an excess of fats in the blood).
For this study, the researchers treated two children — a girl about 2 years old with Leigh syndrome, and a boy nearly age 6 with MELAS — with daily, oral doses of everolimus.
In the girl, the cause of the disease was identified as a mutation in both copies — one inherited from the mother and the other from the father — of the NDUFS4 gene.
At the time she started everolimus, by age 2, she was no longer able to crawl, stand, or cruise, and required a tracheostomy (opening in the neck, where a tube is placed through the windpipe to assist breathing) and gastrostomy (in which a tube is inserted in the stomach to deliver food).
Six months after initiating treatment, her brain MRI showed improvements with a reduction of lesions. After 19 months of treatment, the child was walking independently, although in a slightly uncoordinated manner, speaking in sentences, and no longer required gastrostomy.
Her gross motor function scores (GMFM‐88) improved from 48.8% to 83.8% by the age of 44 months (3.7 years). Nearly two years after starting on everolimus, MRI findings remained improved except for a new abnormal signal in the the medulla (a region in the brain).
Her condition continued to improve and, by age 47 months (just less than 4 years of age), her motor skills reached a score of 84.5%.
For the boy, the treatment was not effective.
Just before starting on everolimus, at age 66 months (5.5 years), the boy had a lower muscle tone, was apathetic, and had seizures. He also was gastrostomy‐dependent, and was unable to stand or walk. His GMFM‐88 score was 11.8%.
Even with everoliums treatment, the boy’s condition continued to deteriorate, both clinically and in terms of brain degeneration, as seen on MRI. He eventually died at age 79 months.
“Our experience with these two children suggests that some, but not all, patients with mitochondrial disease will respond to treatment with mTOR inhibitors. Identifying factors that distinguish responders from nonresponders should allow us to maximize the therapeutic benefits by targeting the responder subgroup while minimizing the potential risks by sparing the nonresponder subgroup,” the researchers said.