Inhibiting an overabundant enzyme saved a key component of a brain signaling pathway that is vital for motor control in a new mouse study, bolstering the prospects for the biotechs currently targeting the enzyme as a treatment for Parkinson’s disease.
Mice with the same genetic mutation that can cause Parkinson’s in humans were fed an inhibitor of the LRRK2 enzyme for three months, which caused vital cell structures called cilia to regrow on rare brain cells that protect neurons. The results were published in Science Signaling on July 1.
If the inhibitor has the same effect in humans and is given early enough in disease development, it should stabilize patients and maybe even improve their symptoms, Suzanne Pfeffer, Ph.D., senior author of the study and a biochemist at Stanford University School of Medicine, told Fierce Biotech in an interview.
“I'm so excited that there are multiple biotech companies in this space already in phase two clinical trials,” Pfeffer added. “It's just so hopeful for patients.”
One such company is Denali Therapeutics, which is running a phase 2 trial of LRRK2 inhibitor DNL151 in partnership with Biogen. Another is Neuron23, which has a phase 2 asset of its own and just raised a $93.5 million series D a couple of weeks ago.
Most cases of Parkinson’s are idiopathic, meaning the cause is unknown. But several genetic mutations can also lead to the neurodegenerative disease, and about 20 to 25% of cases have a genetic cause, Pfeffer said.
One such mutation occurs in the gene that codes for LRRK2, and can result in levels of the enzyme that are two or three times higher than normal. Too much LRRK2 disrupts the formation of little projections called cilia on brain cells called interneurons. These cilia operate like antennae to receive signals from the surrounding environment.
Normally, dopamine neurons in the brain release a signaling protein called Sonic hedgehog (named after the video game character) to instruct interneurons to make protective molecules. Without this protection, dopamine neurons—vital for coordinating motor control—die off over time, leading to the tremors and other movement dysfunction that is characteristic of Parkinson’s. If LRRK2 destroys the cilia of interneurons, the cells can’t detect the hedgehog signal and won’t help protect the neurons.
“We discovered a few years ago that in genetic Parkinson's, in six different mouse models, about half of those interneurons just lose their cilia altogether,” Pfeffer said. “And that decreases the production of these protective factors.”
Pfeffer’s team had previously tried treating these mice with LRRK2 inhibitors for two weeks, but saw no regrowth of cilia.
“Usually, cilia grow and shrink with the cell cycle,” Pfeffer said. “But these neurons are not dividing.” That meant it could be the case that neurons are incapable of ever regaining lost cilia.
But rather than give up, Pfeffer said she was inspired by a 2023 study showing that some other neurons can grow new cilia on a 12-hour cycle, renewing hope that it would be possible for her interneurons to do so too. Ultimately, three months of treatment proved to be long enough for the cilia to be almost entirely restored.
“We just didn't give up, because we also knew that if the cilia were key and they didn't regrow, that the companies working in this space were not going to come up with a cure,” Pfeffer said. “And sure enough, it worked.”