Eureka Staff

Gray Matters: A New Class of Inhibitors Target a PD Gene (Video)

Parkinson's disease is not considered a genetic disorder. So why are LRRK2 mutations such a hot area in PD research? Our live coverage at SfN 2018 continues.

The hallmark symptoms of Parkinson's disease--tremors, muscular rigidity--are known to many. What is not well-understood are the complex combination of genetic components, environmental exposures and unknown factors that are behind the 10 million people living with Parkinson's worldwide.

While this has obviously complicated efforts to develop therapies that help slow progression of the disease, or prevent it entirely, there are some new avenues of research that look particularly promising. One of them involves the protein LRRK2 (pronouned Lark Two), which is the greatest known contributor to Parkinson's disease. LRRK2 is an enzyme that has many functions within a cell – from supporting efforts to move things around inside the cell to helping to keep the power on (involved with mitochondrial function). Mutations in the LRRK2 gene represent only one to two percent of total Parkinson's cases, but in certain ethnic groups the incidence is much higher. Changes in the LRRK2 gene (predominantly the mutation scientists know as G2019S) account for 15 to 20 percent of cases in Ashkenazi Jews and about 40 percent of cases in North African Arab Berbers.

Fortunately, LRRK2 is considered to be a druggable target using small-molecule proteins known as kinase inhibitors. Moreover, destroying the activity of an errant protein is often easier than restoring activity. There are now several LRRK2 inhibitors in development, including PF-360 which Charles River, in partnership with the Michael J. Fox Foundation for Parkinson's Research (MJFF) helped test. Two posters being presented at this week's Society for Neuroscience meeting in San Diego describe some of the preclinical work done to assess the efficacy of PF-360. The studies used cell-based assays to understand how LRRK2 inhibitors influence function in models of PD, and demonstrate dose-related inhibition of LRRK2 activity in the brain. They also looked at potential off-target effects that at one point nearly shelved the LRRK2 target.

A few years ago, researchers published preclinical findings showing a LRRK2 inhibitor led to abnormal changes in lung tissue. The MJFF stepped in and brought together three competing companies developing LRRK2 drugs for Parkinson's  to form the LRRK2 Safety Initiative. The collaboration eventually demonstrated that LRRK2 inhibitors were safe for human testing, which allowed continued investment and research.

The studies that Charles River presented this week looked at dose-response efficacy of the PF-360 compound in two different mouse models. They also looked at whether the LRRK2 inhibitor changed the lung phenotype in rats. "Using the unique capabilities that we have we were able to both look at the central effects of LRRK2 inhibition and demonstrate target engagement, but also use our pathology expertise to look at potential off-target side effects," said Nicholas Moore, PhD, Principal Scientific Advisor for Charles River's CNS Drug Discovery efforts.

You can learn more about these new inhibitors by watching Gray Matters, which is highlighting hot topics at this year's SfN meeting. Also, check out our previous installments of Gray Matters where we covered Batten disease and functional ultrasound in preclinical CNS research. You can also learn more about Parkinson's by reading this recent article in FierceBiotech that describes our ongoing work on LRRK2 inhibitors.