CHOP gene therapy expert fine-tunes protein signals, improves motor function and reduces brain shrinkage in a neurological disorder

IMAGE:Beverly L. Davidson, Ph.D., a gene therapy expert, is the director of The Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia. view more

Credit: The Children's Hospital of Philadelphia

By adjusting the levels of a key signaling protein, researchers improved motor function and brain abnormalities in experimental animals with a form of Huntington's disease, a severe neurodegenerative disorder. The new findings may lay the groundwork of a novel treatment for people with this fatal, progressive disease.

"This research shows the intricate workings of a biological pathway crucial to the development of Huntington's disease, and is highly relevant to drug development," said study leader Beverly L. Davidson, Ph.D., director of The Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia (CHOP). "Our results in animals open the door to a promising potential therapy, based on carefully manipulating the dysregulated pathway to treat this devastating human 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.

The study team published its results online Dec. 31 in the journal Neuron.

Huntington's disease 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) particularly damages a brain region called the striatum, where it interferes with normal cell growth and other fundamental biological events. The resulting disease includes involuntary movements and severe cognitive and emotional disturbances. About 30,000 Americans have Huntington's disease (HD).

Neuroscientists already knew that a signaling protein called mTORC1 that regulates cell growth and metabolism plays a major role in HD. Many researchers have proposed that inhibiting or shutting off the mTORC1 pathway, which interacts with the deleterious mHTT proteins, could help treat HD.

The current study contradicts those assumptions. "We show that the mTORC1 pathway is already impaired in Huntington's disease, and that improving how the pathway functions actually has a protective effect," said Davidson. "However, restoring that pathway must be done very carefully to avoid further harm. It's a 'Goldilocks effect.' You need to restore the mTORC1 level; either too much or too little is detrimental."

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Animal study points to a treatment for Huntington's disease

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