Genetic Insights, New Research Models Help to Drive New Rare Disease Research

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Florian Eichler, MD

While it may not have been called rare disease research by name, Massachusetts General Hospital has been identifying and tracking rare diseases for more than a century, says Florian Eichler, MD, Director of the Center for Rare Neurological Diseases in the Department of Neurology.

In recent years, advances made by the Human Genome Project and next generation sequencing technology have exponentially improved researchers’ ability to identify rare disease-causing genes. The next step is to use this information to develop new treatments.

“The nice thing is that Mass General has cultivated many of the resources needed to accomplish this over the past few decades,” Eichler says.

“We have expert clinicians who have been studying the natural history and clinical course of these diseases for a long time, the basic scientists with laboratory models to help us understand how disease-causing genes function, and molecular biologists to identify pathways to target in developing new treatments.”

“Here in Boston, we have another advantage, which is proximity to industry,” Eichler adds. “For a long time, industry and academia viewed each other as opposite ends of the spectrum. But I think we’re now in a situation where we have more to gain by working together.”

About rare diseases

A rare disease is defined as one that affects less than 200,000 people in the United States. While the number of patients affected by any one rare disease can be relatively low, it is estimated that more than 30 million people in the US have some kind of rare disease. To date, over 7,000 different rare diseases have been identified.

The development of new treatments for rare diseases has been challenged by a lack of funding, particularly because the market for any new treatment is limited by the low number of patients affected. This makes it hard for drug companies to recoup their investment into research and development.

Eichler says that working in this resource-challenged environment has led to new partnership models that bring patient groups, members of industry and clinicians together to share resources and collaborate on solutions.

“When you talk to patients with rare diseases in the clinic, that’s what they want to see. They want physicians, scientists and industry all working together to figure out what’s best for them.”

A compelling success story

Dr. Eichler was recently awarded the hospital’s Martin Research Prize for Clinical Excellence for his role in a study testing a new gene therapy treatment for boys with early stage cerebral adrenoleukodystrophy (ALD).

ALD is a rare genetic disease (depicted in the 1992 movie Lorenzo’s Oil) that results in the destruction of myelin, the protective sheathing around neurons in the brain. It affects 1 in 18,000 people, particularly men and boys, with death or permanent disability typically occurring in 3-5 years from symptom onset.

“In ALD we have this unique situation where boys are born with a normal brain,” Eichler explains. “There are no structural malformations. They grow, sit up, walk, run around, play soccer and are just like any other kid until this disease strikes.”

The only current treatment for ALD is a bone marrow transplant, but there can be a long wait for a compatible donor, and the process often results in complications if the body rejects the transplanted cells.

In their recent study, Eichler and his team treated 17 early stage cerebral ALD patients with an experimental technique that involved removing patients’ own bone marrow cells and using a viral vector to genetically modify the cells to correct the defect that contributes to myelin destruction. The modified cells were then injected back into the patients.

Using the patients’ own cells prevented rejection issues, and two years after the treatment, 15 of the 17 patients were still functioning without major disability or disease progression.

The early results suggest that gene therapy may be a safe and effective treatment for boys with ALD, and has given Eichler reason to hope for better outcomes for his patients.

When Eichler first started at Mass General two decades ago, most of his ALD patients were confined to wheelchairs and many of them were locked in vegetative states for years before succumbing to the disease.”It was a sad clinic,” he acknowledges. “It felt like you were the last step before the graveyard.”

“But now, after this gene therapy trial, it’s wonderful to see these kids coming from all over the world, going to soccer camps, telling me about their travels and the new things they are learning,” he says. “Just being part of that transformative moment makes it all worth it.”

For Eichler, the study is a good example of how a collaborative approach to drug development can pay dividends. “We had great transplant experts across town, neurology experts here at Mass General, a great patient community, and industry partners that were willing and able to take on the manufacturing process.”

“The whole thing never would have happened if all these parties weren’t willing to work together.”

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