Dr. Simonetta Sipione

Associate Professor Department of Pharmacology and Centre for Neuroscience, Faculty of Medicine & Dentistry, University of Alberta
Researcher of the month: 
Aug 2012

Chance encounters

Dr. Simonetta Sipione first came to the University of Alberta (U of A) as a visiting PhD student from Italy, attracted by the university’s outstanding program in lipid research. While there, she met someone. One simple act – moving to Canada to be with the person she loves – set her career on a course that she never imagined.

Today, her laboratory at the U of A is on the verge of a breakthrough that may lead to a promising new therapy that may restore lost motor skills in people with Huntington disease (HD). It may even delay or stop the progression of this inevitably fatal condition.

The breakthrough came from tests in mouse models of HD, conducted at the Sipione Laboratory at U of A and at McMaster University.

HD is an inherited disease that causes brain cells to die. It afflicts 1 in 10,000 Canadians, eventually leading to incapacitation and death. Children of parents with HD have a 50% chance of inheriting the mutant huntingtin gene that causes this deadly disease.

In 2000, opportunity knocked at Dr. Sipione’s door. At the end of her PhD, she was offered a post-doctoral fellowship at the University of Milano (Italy), researching Huntington disease (HD).

“I didn’t really choose to work on this disease. It happened almost by chance, but soon after I started working, I became fascinated by the process of neurodegeneration and the complexity of the molecular phenotype of HD,” she confesses.

“Because every single case of HD is determined by a single genetic mutation, we have relatively precise genetic models that can help to unravel what happens in the brains of patients with HD.”

Lipids in HD

As a post-doctoral fellow, she conducted work showing that HD affects the biochemical pathway leading to cholesterol synthesis. Later, as an independent investigator at the U of A, she went back to this work, strongly believing that lipids play an important role in neurodegeneration. She focused on studying how a deficit of cholesterol in the brain affected cell signalling in mouse models of HD.

While performing these experiments, almost by chance, she and her team of researchers discovered that another lipid, the ganglioside GM1, was even more profoundly affected than cholesterol in mouse models of HD.

The normal brain has plenty of gangliosides and GM1. These lipids are mainly located in the plasma membrane that surrounds every cell. They play an important role in modulating cell response to the environment, the way that cells communicate with each other, and how myelin and neurons interact. 

“Why there is a loss of gangliosides, particularly GM1, in HD is still not completely clear,” says Dr. Sipione. “Because of all of the important functions exerted by gangliosides in the brain, we believe that even a partial reduction in the amount of brain GM1 might have important consequences for the health of neurons.”

Based on this hypothesis, she decided to take a closer look at GM1 and at what happens when levels of GM1 are replenished in a brain with HD. Her laboratory experiments in cell models with HD have shown that increasing the level of GM1 protects brain cells against cell death from environmental stressors and apoptotic stimuli.

“Increasing the level of GM1 improves the ability of brain cells to survive when they are stressed by different factors,” she says. “We have shown that GM1 activates pro-survival signalling pathways in HD cells and triggers specific modifications in mutant huntingtin that decrease its toxicity.”

Surprising results

Since their experimental data in cell lines suggested that GM1 might have a therapeutic effect in animal models of HD, Dr. Sipione and her team decided to administer GM1 to mouse models with motor deficits due to HD. One group of mice received GM1, while the other did not.

Untreated mice struggled in most or all of motor tests during the 4-week experiment. In contrast, the GM1-treated mice improved their motor performance during the first two weeks. In fact, motor skills in the treatment group normalized within days.

“After 14 days of treatment, they were performing as well as normal mice,” says Dr. Sipione, now an associate professor at the U of A and a Canada Research Chair Tier 2 in the Neurobiology of HD and Alberta Innovates-Health Solutions Scholar. “Their motor symptoms were completely abrogated by treatment with GM1.”

The results surprised Dr. Sipione. “When we started in vivo treatment, my expectations were not that high,” she admits. “I thought it would ameliorate symptoms, but the effects of GM1 were much stronger than I had anticipated.”

Motor function in GM1-treated mice declined after 14 days from the end of the treatment and eventually returned to pre-treatment levels, suggesting a need for repeated or continued therapy, she says. Because of the way that GM1 works, Dr. Sipione believes that it may also improve cognitive levels in animal models with HD. Her research team is now pursuing this hypothesis. 

Preliminary data from her laboratory studies suggest that GM1 may do more than correct HD symptoms. “It seems to slow the neurodegenerative process in animal models.”

Even if the translational implications are not as direct in humans as in mice, she says, “knowing that a molecule, GM1, can affect mutant huntingtin toxicity and improve symptoms in mice is very exciting.”

Hope on the horizon

Dr. Sipione hopes that clinical trials in 2 or 3 years will test whether GM1 has the same potential to improve motor function and possibly delay the onset or worsening of symptoms in people with HD.

“It is important to understand that what works in mice does not always work in people,” she cautions.

Most of the laboratory experiments have administered a synthetic form of GM1. In the past, natural GM1 purified from animal brains has been used to treat patients with Parkinson’s disease, Alzheimer’s disease, spinal cord injury, and stroke in clinical trials. Researchers know that it is relatively safe with well-defined side effects. Dr. Sipione hopes that this fact may help to accelerate the start of human clinical trials.

In the laboratory, to achieve maximum effects, GM1 was injected directly into the brains of mice. In humans, GM1 may be administered directly into the central nervous system. There is some precedent for using a centrally injected medication, states Dr. Sipione, citing pain medications for patients with cancer or multiple sclerosis (MS).

“Ideally, we would like to find a way to administer the lipid peripherally, but we still don’t know whether that is possible,” she says.

Dr. Sipione’s research is funded in part by the Huntington Society of Canada, the Canadian Institutes of Health Research and Alberta Innovates-Health Solutions.