Emerging Research on LRRK2 Kinase Inhibitors

Reviewed by: HU Medical Review Board | Last reviewed: March 2017 | Last updated: March 2021

One promising area of research in Parkinson’s disease (PD) is the identification of LRRK2 kinase inhibitors. LRRK2 (leucine-rich repeat kinase 2) is a gene that has instructions that produce a protein. Mutations in the gene are associated with both hereditary and sporadic forms of PD.

The LRRK2 gene was discovered in 2004 and is the greatest known genetic contributor to the development of PD. LRRK2 kinase inhibitors block the action of the mutation.1,2

The role of genetics

The majority of cases of PD are not considered to have an inherited genetic component. While some cases of PD occur in families, 90% of cases are sporadic, meaning they occur without an identified inherited genetic predisposition. By studying families in which PD occurs, scientists have been able to identify genetic mutations common to the disease, such as LRRK2.

After identifying LRRK2, genome-wide association studies were conducted. Genome-wide association studies look at several markers across complete sets of DNA to find genetic variations associated with a specific disease. The genome-wide association studies revealed that the LRRK2 mutation is also present in many sporadic (not familial) cases of PD.

The LRRK2 mutation occurs in about 1% of the population; however, its presence rises up to 40% in some populations, such as in people of Ashkenazi Jewish or Arab-Berber descent.2-4

Gene mutations and lewy bodies

Some mutations in LRRK2, such as the mutation identified as G2019S, increase the aggregation of alpha-synuclein into disease-associated Lewy bodies. Alpha-synuclein is a protein that plays a critical role in the development of PD.

While scientists don’t fully understand the normal function of the protein in the body, they know that in people with PD and some other neurodegenerative diseases, alpha-synuclein clumps together forming aggregates called Lewy bodies.

Scientists believe that Lewy bodies are toxic and cause the death of the neurons (nerve cells). These accumulations of alpha-synuclein appear to spread from one neuron to the next. As the number of Lewy bodies increases in the brain and in the nervous system in the body, the symptoms of PD worsen.1,5

In animal studies, deletion of the LRRK2 gene protected rats from neuron (nerve cell) degeneration. LRRK2 kinase inhibitors also prevent the formation of alpha-synuclein aggregates. This suggests that inhibiting LRRK2 could be a possible approach for PD therapy.6,7

How does LRRK2 lead to Parkinson's?

The exact role of the LRRK2 kinase activity in the development of PD is not fully understood, and researchers continue the search to understand how LRRK2 kinase impacts the development of PD and how the disease might be treated by influencing the LRRK2 pathway.

In a recent study of the LRRK2 inhibitor PF-06447475 in rats, researchers found that the treatment with PF-06447475 strongly reduced the damage to neurons from LRRK2 expression. Some of the rats in the study were wild-type rats – they did not have the LRRK2 mutation. Others were modified to contain the LRRK2 genetic mutation G2019S.

All the rats were then given a virus to deliver alpha-synuclein to mimic PD features, and they were randomized to receive either the treatment with PF-06447475 or a control. The interesting finding is that PF-06447475 was associated with neural protection both in those rats with the genetic mutation and the wild-type rats. This finding was significant because it suggests the treatment may help the majority of people with PD, not just those who have the G2019S mutation.

The trial lasted just four weeks, so additional, longer studies are needed to determine if the neuroprotective effects will continue, or if the damaging effects from alpha-synuclein are just delayed. Also, this trial was conducted using rats, and the therapy may not have the same effect on humans.6,8

What are the side effects?

Some trials have identified side effects with LRRK2 inhibitors, including lung issues.9 The Michael J. Fox Foundation for Parkinson’s Research recently organized the LRRK2 Safety Initiative and brought together researchers from pharmaceutical companies Genentech, Merck, and Pfizer to share data.

This initiative found that while the different compounds each company is studying were associated with changes to lung tissue in non-human primates, these changes are reversible and not associated with any functional problems. This collaboration has enabled the research to continue to move forward, and several drug candidates are continuing to be tested as potential treatments.1

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