Parkinson’s disease drug candidates could help many more people than expected

New findings suggest that drugs already in development for a small percentage of patients could treat most people with the disease.

A protein implicated in a small percentage of Parkinson’s disease cases may actually be a culprit in most instances of the disease, new research reveals. In light of these results, scientists believe niche treatments already in development could help many more people than initially thought.

Parkinson’s disease afflicts an estimated 10 million people worldwide. Existing treatments can lessen the severity of symptoms, which include muscle rigidity, tremors, and speech difficulties, but there is no known cure. In most cases, the cause of the disease is unknown—both genetic and environmental factors seem to play a role.

For about three percent of patients, the cause of the disease can be traced back to a gene mutation that causes the protein LRRK2 to be too active. Drugs are in development to treat this small sliver of the Parkinson’s disease patient population. Until now it was unclear what role, if any, LRRK2 plays in Parkinson’s disease for the approximately 90 percent of patients without a mutation.

Researchers see LRRK2 light up in donated brain tissue


“The LRRK2 protein is generally present in cells in very low amounts, which makes it difficult to study its function or activity,” said J. Timothy Greenamyre, who supervised the study. Greenamyre and his coauthors developed a way to make LRRK2 glow in its activated state. This allowed them to check brain tissue samples donated by both Parkinson’s patients and healthy people to see how active the protein was in each group. The results were clear: LRRK2 was highly active in Parkinson’s patients and not in healthy people.

A fluorescent sensor for LRRK2 activity. Courtesy of the Greenamyre lab.

To figure out how LRRK2 causes Parkinson’s disease when it’s too active, the team looked at models of the disease in rodents. They found that LRRK2 prevents cells from clearing out a protein linked to the formation of Lewy bodies, the structures that form in the nerves of patients with Parkinson’s disease. When the animals were treated with LRRK2-inhibiting drugs designed for patients with gene mutations, the protein didn’t accumulate, and the Lewy bodies didn’t form.

"Our findings suggest that both genetic and environmental causes of Parkinson's disease can be tied back to the activity of LRRK2 protein," said Greenamyre.

Drugs in the pipeline show promise


The researchers’ results make them optimistic that drugs already in the pipeline for patients with genetic mutations could work for many, or even all patients Parkinson’s disease. “If so, this may provide a way to slow or halt the otherwise inevitable progression of the disease,” said Greenamyre. “This is particularly exciting since several companies are working on such drugs, and some are in the early stages of being tested in humans.”

One such company is Denali Therapeutics. In December, the company announced that one of their LRRK2 inhibitor drug candidates was safe and lowered LRRK2 protein activity in healthy volunteers. The company is now conducting further clinical research before starting trials with Parkinson’s disease patients carrying a LRRK2 mutation.

“I hope our work showing the likely utility of such therapies in sporadic Parkinson’s disease further incentivizes these companies to redouble their efforts,” said Greenamyre. “This is an exciting time for people affected by Parkinson’s disease.”

 

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Featured image: Lewy bodies and Lewy neurites. Courtesy of Suraj Rajan