CHOP scientists herald new approach to neurodegenerative diseases

The mTORC1 pathway has been a major focus of some prominent investigators interested in the role that it plays in the development of neurodegenerative diseases. Now a team at Children's Hospital of Philadelphia (CHOP) says they've debunked a common misconception about the pathway and come up with a new and better approach to mTORC1 that has proved promising in an animal model of Huntington's disease.

Beverly Davidson

The assumption, says study leader Beverly Davidson, director of The Center for Cellular and Molecular Therapeutics at CHOP, is that by shutting down the signaling protein called mTORC1--which regulates cell growth and metabolism--you could positively influence the course of the disease. Instead, her research indicates that fine-tuning the activity of the pathway offers the best shot at targeting neurodegenerative conditions like Huntington's, ALS, fragile X and autism. And preclinical evidence suggests that this new approach could also reverse the effects of Huntington's.

In Huntington's, she explains in a statement, a "defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant protein mHTT damages a brain region called the striatum, where it interferes with normal cell growth and other fundamental biological events."

The team developed a gene therapy delivered by bioengineered viruses that spurred the development of regulatory proteins called Rheb and Rhes, which act along the pathway. And in animal models they found that the treatment increased brain volume, improved motor functions and ramped up a natural process that clears away mHTT. Investigators also tracked improvements in metabolic functions like cholesterol levels, dopamine signaling and mitochondrial activity.

"It was particularly exciting to see plasticity in the neurons impaired by mHTT," said Davidson. "This shows that brain cells are capable of responding even after disease onset, and hints at the potential for reversing Huntington's disease."

Davidson's team at CHOP, which has been a pioneer in gene therapy technology with its spinoff Spark Therapeutics, proposes that the animal research work would make an excellent starting point for anyone interested in developing new therapies for neurodegenerative diseases.

But they won't be alone. Just last summer Navitor Pharmaceuticals announced its Series A round with plans to focus on mTORC1. Navitor is basing its R&D plans on the work MIT Professor David Sabatini has done on mTORC1.

- here's the release