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New Therapeutic Target Identified for Leigh Syndrome



LEIGH SYNDROME in an animal knockout model (left) compared with a wild-type mouse. The knockout mouse exhibits the disease phenotype — muscle weakness, lack of coordination or muscle control, weight loss, and hair loss.

Investigators injected an animal model of Leigh syndrome with rapamycin, and found that it attenuated disease progression and ameliorated some of the behavioral symptoms.

Scientists at the University of Washington in Seattle who are studying the rapamycin (mTOR) signaling pathway and its impact on the aging process have made a serendipitous discovery that could have an impact on people born with a Leigh syndrome, the most common (and lethal) mitochondrial disorder.

Reporting in the Nov. 14 online edition of Science, they suggest that targeting the mTOR pathway could be one way of treating the condition. At present, there are no treatments for Leigh syndrome. In theory, the finding could also lead to treatments for other mitochondrial conditions.

The study's senior author, Matt Kaeberlein, PhD, a biologist and associate professor of pathology, is best known for his work with caloric restriction, showing that inhibiting the mTOR pathway kicks into gear the same events that take place with curbing calories; both can increase lifespan in mice — by ten to 15 percent in the case of rapamycin and 30–40 percent for caloric restriction.


His group had screened the genome in yeast to look for genes that influence the response to caloric restriction (less glucose) and found, unexpectedly, that this dietary intervention could suppress the very short lifespans of many yeast mutants defective for normal mitochondrial function. This led his group to speculate that inhibiting mTOR might generally be beneficial when mitochondria aren't working properly, and he wanted to test some of his ideas on animal models of mitochondrial disease. Richard Palmiter, PhD, a neurobiologist and professor of biochemistry at the University of Washington had developed a knockout (KO) mouse that is used as a model of Leigh syndrome. Dr. Palmiter, who is also an investigator with the Howard Hughes Medical Institute, handed over some of his animals. Dr. Kaeberlein and his colleagues set out to see if their findings in mice would mirror what they found in yeast.

Patients with Leigh syndrome are smaller and suffer from muscle weakness, lactic acidosis, and a range of severe neurodegenerative problems. The animal model has many of the same features seen in patients.

The University of Washington investigators injected rapamycin, an mTOR inhibitor, every other day (starting at day 20) and found a 30 to 40 percent increase in lifespan. “This was enough of a change that we thought there may be something important happening,” said Dr. Kaeberlein.

In the next experiment they started medicating the animals on day 10 and treating them every day. This time, there was a two- to three-fold increase in survival. And many of the treated animals didn't show any of the behavioral problems that are normally seen in the mutant animals. At death, they were able to see that the neurodegenerative components of Leigh syndrome were attenuated. There was reduced brain inflammation and the treatment prevented the characteristic brain lesions associated with the genetic mutation. The treated animals breathed normally. They did not press their legs tightly against their bodies, slumping over. They could also carry out tasks their untreated littermates could not, including balancing and running on a rotarod.

The untreated mutant mice lived on average for 50 days. The treated males in this study lived on average for 114 days; the females, 111 days. The last treated animal standing was 269 days old.

Leigh syndrome is associated with mitochondrial complex I deficiency. The most obvious explanation for this enhanced lifespan was that rapamycin corrected this imbalance. But that wasn't the case. Rapamycin did not fix this deficiency, said Dr. Kaeberlein. The investigators looked at hundreds of metabolites in the energy pathway and compared changes in the treated and untreated Leigh syndrome mice. What they did find was that the treated animals burned more amino acids and fats for energy rather than through the more traditional energy source, glucose. This was a more efficient method as it eliminated the problem of exposure to glucose breakdown products, including lactate, which can be toxic to cells.

“We think that rapamycin is shifting metabolism away from the primary mechanism of burning glucose to a state that is similar to starvation,” said Dr. Kaeberlein. “I am excited that we have a chance to understand on a metabolic level what is going wrong in Leigh syndrome.” He suspects that he has tapped into a general mechanism that could benefit many types of mitochondrial problems. If so, mTOR inhibitors might be useful for a range of mitochondrial disorders.

The researchers are now trying to figure out how rapamycin rescues mice with Leigh syndrome. They are also testing other interventions to reverse the phenotype in this mouse model.

The next step, of course, is to design a trial to study rapamycin in patients with Leigh syndrome. The Food and Drug Administration approved the drug — marketed as sirolimus — to protect against organ transplant rejection and rare forms of cancer. “We are optimistic that rapamycin (or the development of new drugs that inhibit the mTOR pathway) has potential for kids with Leigh syndrome,” said Dr. Kaeberlein.

“It's a nice piece of work,” said Dr. Palmiter. “They saw that it worked in yeast and they wanted to try it in mice. Rapamycin clearly allowed the animals to live longer.”

Study co-author Philip Morgan, MD, a professor of anesthesiology and pain medicine at Seattle Children's Hospital, runs a laboratory on mitochondrial disorders with his wife, Margaret Sedensky, MD. They did all of the biochemical work in the new study on rapamycin and Leigh syndrome. They are continuing to use the mouse model to test the effects of rapamycin on specific hard-hit brain regions. He said that it is too early for doctors to think about recommending the drug to families with a child with Leigh syndrome. “A lot more work needs to be done,” he said. “The finding offers us a new mechanism to target. It is incredibly exciting but way too early to use it in patients.”


The mitochondrial genome has its own set of genes and proteins that are also prone to mutations and mishaps. While there are mitochondrial mutations that trigger a range of diseases, including Leigh syndrome, there are many conditions such as Parkinson's disease and Alzheimer's that may have roots in less obvious mitochondrial defects. The body has its own system of clearing out damaged mitochondria.

Michael T. Lotze, MD, a professor of immunology, and vice chair of research at the University of Pittsburgh Cancer Institute, said that the “rapamycin may restore sufficient mitochondrial functioning” and work to clean out the cellular debris. “It is a regulator of autophagy in cells,” he said. “Kids with these terrible syndromes have inadequate ways of clearing out dysfunctional mitochondria. We have been looking for ways to clear out the bad mitochondria and make room for the good ones.”

“The scientists who conducted the study claim that rapamycin worked by changing metabolism in these sick mice,” he said. “What would have been cellular waste turns into useful energy. The hope is that the finding could pave the way to a treatment for Leigh syndrome. That would be good.”

But another neurologist who treats mitochondrial disorders in children expressed some reservations about the finding. “What works in an animal doesn't always work in humans,” said Russell P. Saneto, DO, PhD, an associate professor of neurology and adjunct associate professor of pediatrics at Seattle Children's Hospital. “It's a good sign — it offers the possibility of a treatment — but we don't know if it will work.”


DR. MATT KAEBERLEIN: “We think that rapamycin is shifting metabolism away from the primary mechanism of burning glucose to a state that is similar to starvation. I am excited that we have a chance to understand on a metabolic level what is going wrong in Leigh syndrome.”

“Initially it is not going to be the drug that we put kids on,” he added, “because [as an immunosuppressant], it could have significant side effects.”

Investigators are researching other options with different mechanisms. Dr. Saneto is involved in a clinical trial testing another compound, EPI-743, for Leigh syndrome. Through a redox-based mechanism, EPI-743 augments endogenous glutathione biosynthesis — essential for the control of oxidative stress. In a 2012 report in Molecular Genetics and Metabolism, all 10 children in an open-label study showed a reversal of their disease progression over the 180-day study period. The study investigators, including Dr. Saneto, have enrolled another 30 patients.


•. Johnson SC, Yanos ME, Kayser EB, et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 2013; E-pub 2013 Nov 14.
    •. Martinelli D, Catteruccia M, Piemonte F, et al. EPI-743 reverses the progression of the pediatric mitochondrial disease—genetically defined Leigh syndrome. Mol Genet Metab 2012;107(3):383–388.
    •. NIH Information on Leigh syndrome: