Though many researchers explored topics of genetics and genomics over the years, the two fields are now emerging as key players within the realm of health and medicine. One important use is the understanding of genetics and disease progression: why certain people develop conditions and others don’t, how gene variants alter patient outcomes. LRRK2 gene mutations are closely linked to Parkinson’s disease. But studies showed that LRRK2-inhibitors might cause organ damage.

So, researchers wondered how patients with naturally low levels of LRRK2 fared. Ultimately, their study suggests that inhibitor therapies are safe for treating patients. Check out the full study in Nature Medicine.

LRRK2 Genes

The leucine-rich repeat kinase 2 (LRRK2) gene instructs the body on how to create the protein dardarin. According to the Genetics Home Reference, the gene is most active within the brain and other tissues. Leucine-rich refers to the fact that dardarin consists of a lot of leucine, a protein building block. Multiple studies in the past link LRRK2 mutations with the development of Parkinson’s disease.

LRRK2 Inhibitors

Currently, there are three separate Phase I trials on these inhibitors:

• DNL201: a randomized, placebo-controlled, double-blind trial which completed a few months ago. This studied the toxicity, safety, and tolerability of Denali Therapeutic’s orally-taken LRRK2 inhibitors.
• DNL151: a randomized, placebo-controlled, double-blind trial which is also studying inhibitors from Denali Therapeutics.
• NCT03976349: this randomized, triple-masked study is examining the safety and tolerability of Biogen’s ASO therapy, BIIB094. The therapy targets the micro RNA (mRNA) of LRRK2 to degrade it, reducing levels in the body.

Researchers questioned whether LRRK2-inhibitors would be safe and effective treatment options for patients with Parkinson’s disease. They were unsure whether significantly lowering LRRK2 levels would result in poor outcomes or organ damage. This concern resulted from pre-clinical studies on genetically modified mice and primates; when they lacked the studied gene, they experienced kidney, liver, and lung abnormalities.

Genetic Studies and Genome Databases

The Genome Aggregation Database (gnomAD), a large example of a genetic study, holds genomic analyses of over 140,000 people. According to Dr. James Ware, PhD:

“The gnomAD resource is proving hugely valuable to understand which genes are important in human health and disease, and to understand which specific variants in those genes cause problems.”

So, researchers thought that examining the data within gnomAD would help determine the relationship between low LRRK2 levels and poor health outcomes. If they were related, it would suggest that inhibitors were unsafe. If they were unrelated, it would suggest the tolerability of LRRK2-inhibitor treatment.

Using gnomAD, researchers looked for natural gene mutations (called loss of function mutations) that decreased the amount of LRRK2. Additionally, researchers sourced data from 4 million users from 23andMe, and 46,062 individuals within the UK Biobank. Ultimately, they discovered 1,455 individuals that met their needs.

Next, researchers examined whether these individuals had any lung, kidney, or liver damage, or poor health outcomes leading to a shorter life. However, researchers found no correlation. As a result, their findings suggest that LRRK2-inhibitors are most likely safe and well-tolerated for patients with Parkinson’s disease.

Read the original article here.