June 21, 2022
Doris Doudet & Allyson J. Bennett
Parkinson’s illness (PD) is a outstanding neurodegenerative illness that impacts greater than 10 million folks worldwide. It’s the second commonest neurodegenerative illness after Alzheimer’s illness. PD is related to well-known motor signs akin to tremors, sluggish actions and elevated danger of falling but additionally a wide range of non-motor signs together with temper, sleep problems and constipation to call a couple of. Medication and surgical options enable some management of the signs however are usually not a treatment and the illness development and cell dying continues. The chance of creating PD will increase with growing old. Nevertheless, a minority of youthful instances have been linked to genetic predisposition. One of many linked genes is the LRRK2 gene. LRRK2 overgrowth impacts the effectivity of the cell’s waste administration system, particularly of undesirable or incorrectly produced proteins, resulting in a rise and accumulation of poisonous by-products that may result in accelerated cell dying.
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.
Read more at: https://www.science.org/content/article/experimental-drug-targets-early-stages-parkinson-s