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An experimental drug is raising new hopes for those with Parkinson’s disease. So far, the compound has only been tested in animals and in an initial safety assessment in humans. But results show it inhibits a cellular pathway that gives rise to the disease, which researchers have been working to target for nearly 20 years. Investigators are now launching expanded clinical trials.

“This is a very, very important step forward,” says Patrick Lewis, a neuroscientist who studies the mechanisms of Parkinson’s at the University of London’s Royal Veterinary College. If further tests prove the compound is effective in humans, says Lewis, who was not involved with the new study, it would likely be given to patients as soon as they exhibit the first signs of developing the progressive disorder. “The hope is that [the new drug] would slow down the progression of disease.”

Parkinson’s affects as many as 10 million people worldwide. It results when cells in the brain that produce the neurotransmitter dopamine stop working or die. Over time this causes a widespread decline in brain function, leading to shaking and loss of muscle control. Current drugs can help replace lost dopamine and reduce symptoms, but no therapies slow or halt disease progression itself.

The new study focuses on a gene called leucine-rich repeat kinase 2 (LRRK2). People with mutations in this gene are at high risk for developing Parkinson’s. Among other roles, LRRK2 modifies a suite of proteins called Rab guanosine triphosphates, which act like air traffic controllers, orchestrating the flow of proteins in and out of cells.

The mutations kick Rab into overdrive and reduce the efficiency of cellular structures called lysosomes, which chew up and recycle unwanted proteins. This creates a buildup of toxic byproducts that can kill neurons and lead to Parkinson’s, says Carole Ho, chief medical officer of Denali Therapeutics, a biotech startup in California.

In 2012, researchers at Genentech discovered a candidate drug that inhibits LRRK2. Scientists at Denali later tweaked the structure to create a drug called DNL201, which can be taken by mouth. That led to the animal studies that showed it blocks LRRK2, reduces Rab, and improves lysosomal function.

But animal studies with the drug also revealed that tissues in lungs and kidney—which normally produce high levels of LRRK2’s protein, called dardarin—wound up with larger than normal vesicles, small fluid-filled containers inside cells. That raised “significant concerns” that DNL201 would cause side effects in people, Lewis says.

To test those concerns, the authors behind the new study gave DNL201 to rats, macaque monkeys, and 150 human volunteers for 28 days. The idea was to reduce dardarin levels enough to restore Rab function to normal, but not so much as to block dardarin’s function completely, says Danna Jennings, a neurologist at Denali, who led the work.

In the animals, the drug reduced Rab levels and boosted lysosomal function. It was well tolerated when given to 122 healthy volunteers and 28 Parkinson’s patients, who showed no signs of lung or kidney problems, or other side effects. Tracking of chemical markers suggested DNL201 also reduced LRRK2 levels in the blood, and that the compound was active in the brain, the researchers report today in Science Translational Medicine. This early-stage clinical trial was not designed to assess whether the compound was effective in slowing Parkinson’s disease.

“It’s exciting,” says Tanya Simuni, a neurologist at Northwestern University. The results, she says, are in line with the notion that inhibiting LRRK2’s work could restore lysosomal function and block progression of Parkinson’s. “It certainly gives us hope.” That said, both Lewis and Simuni say it seems doubtful the new drug will reverse symptoms in patients with the disease, because it’s unlikely to restore dopamine-producing neurons that have already been damaged or killed.

Denali officials say they also completed human safety trials with a closely related drug, DNL151, which also inhibits LRRK2. But they have yet to release the clinical trial data on that compound. Tests show DNL151 lasts longer in the blood than DNL201, which could reduce how often patients must take it.

The company is already working on additional clinical trials for DNL151. The studies will give patients the drug for up to 48 weeks, which should help researchers determine whether chronic administration of the drug produces side effects in the lungs, kidneys, or elsewhere, Jennings says.

Correction, 8 June, 5:30 p.m.: An earlier version of this story mistakenly said Denali Therapeutics is planning a second stage clinical trial for DNL201. Instead, Denali researchers are pursuing two clinical trials of DNL151.

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