Researchers Lay Groundwork for Novel Therapy for Huntington's Disease

New findings by researchers in the Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia suggest that an intricate pathway crucial to the development of Huntington’s disease (HD) rests on a “biological teeter-totter” that when carefully balanced could help to control this devastating neurodegenerative disorder.

HD affects about 30,000 Americans and is an incurable, inherited disease entailing progressive loss of brain cells and motor function, usually beginning in midlife. A defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant HTT protein (mHTT) damages a brain region called the striatum, resulting in involuntary movements and severe cognitive and emotional disturbances. A key signaling protein called mTORC1 that regulates cell growth and metabolism plays a major role in HD.

In their experiments, study leader Beverly L. Davidson, PhD, director of the CCMT, and co-investigators adjusted levels of mTORC1 in mice bred to model features of HD. They injected bioengineered viruses as a gene therapy tool to carry DNA that directed the production of regulatory proteins called Rheb and Rhes that act along the mTORC1 pathway. After the researchers restored mTORC1 activity to more normal levels, brain areas that had begun to atrophy recovered volume and permitted better motor function.

“It was particularly exciting to see plasticity in the neurons impaired by mHTT,” said Dr. Davidson, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. “This shows that brain cells are capable of responding even after disease onset and hints at the potential for reversing Huntington’s disease.”

She added that restoring proper balance to these delicate biological processes may offer even broader benefits in treating other neurological diseases, such as amyotrophic lateral sclerosis (ALS), fragile X mental retardation, and autism. Fragile X mental retardation and autism both feature overactive mTORC1 activity, while mTORC1 is reduced in ALS and HD.

“This pathway is poised on a biological teeter-totter, and our work highlights that it’s essential to control its activity to find the appropriate balance for each disease,” Dr. Davidson said.

In the future, the research team will focus on increasing their understanding of how they can carefully manipulate the dysregulated pathway to treat HD, with the goal of finding a potential drug therapy. Much work remains, as researchers must identify drug candidates that appropriately activate the mTORC1 pathway. Although gene therapy vectors were used for this research, Dr. Davidson envisions developing a small molecule that can appropriately modulate this pathway. Such a treatment might be combined with a gene therapy approach, also being pursued by her team and other groups, delivered directly to the brain to curtail mHTT expression.

The study team published its results online Dec. 31 in the journal Neuron. They performed a substantial part of this research in Dr. Davidson’s laboratory at the University of Iowa, before she and many of her colleagues moved to CHOP in 2014. John H. Lee, the paper’s first author, remains at the University of Iowa, where he is completing his MD/PhD training. For more information about their research, a press release is available. The National Institutes of Health and the Roy J. Carver Trust supported this study.