Treatments Targeting LRRK2 Not Likely to Damage Organs, Study Finds

People carrying gene variants that lower leucine-rich repeat kinase 2 (LRRK2) levels — an enzyme whose mutated form is one of the most common genetic causes of Parkinson’s disease — live as long as those without such variants, and show no related lung, liver or kidney damage, results of a large genetic study show.

These findings give support to recent clinical trials testing molecules that block the activity of the LRRK2 kinase, and to their potential as disease-modifying therapies for people with Parkinson’s.

The study, “The effect of LRRK2 loss-of-function variants in humans,” was published in the journal Nature Medicine.

Large-scale genetic studies of people are key for pinpointing gene variants that increase the risk for certain diseases, including Parkinson’s. The Genome Aggregation Database (gnomAD) is one of such study, with a genomic analysis of more than 140,000 individuals worldwide.

“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, and it is already in daily use in genetic testing laboratories around the world,” James Ware, PhD, with the National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, and a study author, said in a news story.

Previous genomic studies found that variants enhancing the function of the LRRK2 gene are among the most frequent genetic causes linked to a significantly increase in a person’s risk of inherited Parkinson’s disease. Variants in this gene are also are associated with a higher risk of sporadic Parkinson’s, this disease’s most common form.

LRRK2 is therefore a prominent treatment target, and three Phase 1 clinical trials are testing LRRK2 inhibitors. Two studies are working with Denali Therapeutic’s oral LRRK2 inhibitors — the recently completed DNL201 (NCT03710707) and the ongoing DNL151  (NCT04056689) — and a third trial (NCT03976349) is assessing BIIB094, by Biogen. (This study may be enrolling eligible patients; information is available here.)

BIIB094 is an antisense oligonucleotide (ASO), small molecules designed to bind to messenger RNA (mRNA) — a molecule generated from DNA that contains the information to make proteins. In this case, BIIB094 targets the mRNA of LRRK2 to trigger its degradation, thereby reducing the levels of LRRK2 and potentially slowing disease progression.

However, preclinical studies raised concerns about the toxicity of blocking LRRK2. Data from mice and primates genetically engineered to lack the LRRK2 gene showed this resulted in lung, kidney and liver abnormalities.

Genetic databases like gnomAD can help in understanding whether similar side effects occur in humans.

“Large genetic databases are increasingly giving us a powerful insight into the likely impact of certain drugs. If we see that genetic variants that naturally reduce the amount of protein in our body do not result in severe diseases, we can be more confident that targeting that protein therapeutically will also be safe,” said Nicky Whiffin, PhD  the study’s lead author.

Researchers surveyed gnomAD for natural gene variants that reduce the amount of LRRK2 protein (called loss of function variants), and assessed whether they were linked with detrimental effects. They also looked for loss of function variants in a genetic database of 46,062 unrelated European individuals from the UK Biobank, and from genetic records (with consent) of over 4 million people with the private gene analysis company 23andMe.

In total, they identified 1,455 individuals carrying loss of function variants in the LRRK2 gene and who subsequently had lower levels of LRRK2.

They next determined whether low levels of LRRK2 led to a shorter lifespan or severe problems with the lungs, liver or kidneys.

Loss of function variants in the LRRK2 gene were found to have no impact on longevity, with carriers of the variants being of similar ages to those without the variants.

Likewise, a review of questionnaires and electronic health records from all three genetic databases showed no significant associations with any lung, liver or kidney problems among those carrying LRRK2 loss of function variants.

“Our results demonstrate the value of large-scale genomic databases and phenotyping [disease evaluation] of human loss-of-function carriers for target validation in drug discovery,” the researchers wrote.

The findings support the potential safety of LRRK2 inhibitors, and their possible use as disease-modifying treatments for Parkinson’s disease.

This study is part of a collection of seven studies involving leading academic institutions, such as the Broad Institute of MIT & Harvard and Imperial College London, using the genetic database gnomAD to discover genetic variants that may lead to disease. Additional studies were published in the journals Nature and Nature Communications.

“This collection of papers highlights just some of the many uses for this powerful resource, which will become even more informative as the dataset gets bigger,” Ware said.

“The gnomAD resource is an enormous team effort. More than 100 different research teams have shared data from over 140,000 people. This sort of collaboration and sharing allows to do work that no single team could manage in isolation,” he added.