Protein Bioengineering Applications May Offer a Treatment for Huntington’s Disease, Improving Motor Function and Reducing Brain Shrinkage

This new findings may become the basis of a new treatment for individuals suffering from this lethal, 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, PhD, director of The Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia (CHOP; PA, USA). “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.”

Dr. Davidson added that restoring a correct balance to these delicate biologic mechanisms may offer even broader benefits in treating other neurological diseases, such as amyotrophic lateral sclerosis (ALS), autism, and fragile X mental retardation. The investigators published the study’s findings online December 31, 2014, in the journal Neuron, and will appear in print January 21, 2015.

HD is an incurable, inherited disease entailing progressive loss of brain cells and motor function, typically beginning in midlife. A defective gene produces repeated copies of a protein called huntingtin (HTT). The mutant HTT protein (mHTT) specifically damages a brain region called the striatum, where it interferes with normal cell growth and other essential biologic events. The resulting disease includes involuntary movements and severe cognitive and emotional disturbances.

Neuroscientists have already determined that a signaling protein called mTORC1 that controls cell growth and metabolism plays a chief role in HD. Many researchers have proposed that suppressing or inactivating the mTORC1 (mammalian target of rapamycin complex 1) pathway, which interacts with the toxic mHTT proteins, could help treat HD. The current study challenges those suppositions. “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 Dr. 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.”

In research mice bred to model characteristics of HD, the scientists injected bioengineered viruses as a gene therapy strategy to transport DNA that directed the production of regulatory proteins called Rheb and Rhes. Both proteins act along the mTORC1 pathway. The treated mice had improvements in brain volume and in their movements. The mice had improved metabolic functions as well, such as dopamine signaling, cholesterol levels, and mitochondrial activity (an indicator of cellular energy production). There also were increases in autophagy, an organism’s tidying mechanism that clears out and recycles mHTT and other proteins.

“It was particularly exciting to see plasticity in the neurons impaired by mHTT,” said Dr. Davidson, noting that in the HD mice, brain regions that had begun to atrophy recovered volume and allowed enhanced motor function after the researchers restored mTORC1 activity to more normal levels. “This shows that brain cells are capable of responding even after disease onset, and hints at the potential for reversing Huntington’s disease.”

Further research is needed, according to the investigators, remains to convert these scientific findings into a clinical treatment. Researchers must identify drug candidates that appropriately activate the mTORC1 pathway. Although gene therapy vectors delivered to brain were used for this research, Dr. Davidson foresees developing a small molecule that can effectively modulate this pathway. Such a treatment might be combined with a gene therapy approach, also being pursued by her colleagues and other groups, delivered directly to the brain to suppress mHTT expression.

More widely, Dr. Davidson reported, restoring activity to normal levels may help patients with other neurologic diseases. 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,” she concluded, “and our work highlights that it’s essential to control its activity to find the appropriate balance for each disease.”

Children’s ‘Hospital of Philadelphia was established in 1855 as the United States’ first pediatric hospital.

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