June 21, 2022
Doris Doudet & Allyson J. Bennett
Parkinson’s disease (PD) is a prominent neurodegenerative disease that affects more than 10 million people worldwide. It is the second most common neurodegenerative disease after Alzheimer’s disease. PD is associated with well-known motor symptoms such as tremor, slowness of movement and increased risks of falls but also a variety of non-motor symptoms including mood, sleep disorders and constipation to cite a few. Drugs and surgical options permit some control of the symptoms but are not a cure and the disease progression and cell death continue. Risk of developing PD increases with aging. A minority of younger cases, however, have been linked to genetic predisposition. One of the linked genes is the LRRK2 gene. LRRK2 overdrive affects the efficiency of the cell’s garbage handling system, especially of unwanted or mis-produced proteins, leading to an increase and accumulation in toxic byproducts that can lead to accelerated cell death.
Discovery and development of potential new treatment
A new class of drugs, called DNL201 or DNL151, was recently developed that appears to have the ability to reduce the toxic accumulation by modulating the action of LRRK2. While these DNL drugs are not expected to reverse the course of PD, it is hoped that, by reducing the cells’ exposure to their own toxic products, the cells will not suffer early and accelerated death. If this happens it would significantly slow down the progression of the disease and improve patients’ prognosis and lives.
Animal studies and preclinical results
The new drugs have been tested in rats and monkeys to assess safety. The animal tests are necessary to determine potential unwanted and unanticipated side effects of decreasing LRRK2 levels. From these animal studies, doses of DNL that could reduce toxic byproducts in the brain while maintaining adequate LRRK2 levels in lungs and kidneys were determined. The results of the testing then led to early clinical trials aimed at confirming safety in healthy volunteers who served as control participants and a few PD patients. Both groups took the drugs for as much as a month. Longer exposure to the drug is of course needed both in animals and humans to replicate these safety findings but also to start evaluating efficacy and determine whether DNL will fulfill the promises and hopes the preclinical studies have raised.
While the results of these early trials look promising, many further studies need to be conducted in both humans and non humans to confirm long term mechanism of action, long term safety and furthermore, efficacy. The role of mice, rats and even non human primates engineered with the same LRRK2 abnormalities as the PD patients will be crucial to evaluate the efficacy of the drug in a timely fashion, a feat that will be difficult to achieve solely in the small human LRRK2-identified population. Furthermore, other models of the disease (i.e. non-LRRK2 induced) in mice, rats, primates or other species like fruit flies can also be instrumental in investigating if improving “garbage disposal” in cells without an obvious LRRK2 deficit may also contribute to slowing disease progression by improving cell metabolism and survival.
This research demonstrates the vital role of animal research in understanding the molecular mechanisms underlying complex diseases like PD. That critical information is needed as the foundation for developing new treatments. The goal? Improved quality of life in those affected by a devastating degenerative disease, including one of the most vulnerable communities—the elderly.