Developing disease-modifying therapies in Parkinson’s Disease: The buzz about LRRK2 kinase inhibitors

Parkinson’s disease is caused by a complex combination of genetic components (many of which we know about), environmental exposures (less well understood), and lest we not forget the ever-frustrating element of bad luck that we do not understand. However, the complexity of causation should not diminish hope for identifying therapies that slow or block disease progression. Therapies that would slow or halt disease progression we call disease-modifying, and these have not yet been found in Parkinson’s disease. But we think we are close. This is because of the possible existence of so-called bottlenecks in the disease pathway, or points of convergence that disease must route through in order to change and worsen. Many laboratories are focused on identifying these critical points of convergence and the biological factors that drive them forward. The thought is that positive manipulation of these biological factors will slow disease progression, thereby ‘modifying’ disease.

While there are hundreds or thousands of plausible biological factors that have been identified in different laboratories through the years in Parkinson’s disease research, there are limited resources to be able to test them all in patients. Thus, it is important to try and gauge the importance of a particular biological factor in disease progression. We have a few tricks to help with this task: first, we have genetic studies that find genes that encode proteins that we know play some role in disease. Through these genetic studies, we now have twenty or thirty genes that encode as many proteins that we think are important in Parkinson’s disease. Second, we can look at whether these proteins identified in genetic studies are different in people with Parkinson’s disease versus those without the disease. Correcting that difference may impact disease progression. Third, we have model systems that allow direct testing of whether the protein of interest may be driving particular aspects of cellular pathways linked to Parkinson’s disease. Recent studies have demonstrated that a protein called LRRK2 (pronounced lark two) satisfies all three of these domains as a crucial factor in Parkinson’s disease.

Unfortunately, the identification of a protein critical to disease is not necessarily followed by a cure for the disease. This is because most proteins make terrible targets for the types of molecules and biologics that can be developed as drugs. In the case of LRRK2, we are lucky. LRRK2 belongs to a class of protein that are known to be ‘druggable’ targets, most famously through a type of small molecule called “kinase inhibitors” that can be engineered into pills. The second lucky aspect of LRRK2 in Parkinson’s disease is that the evidence from genetic studies, from the human biomarker studies, and from the model systems, all suggest elevated LRRK2 activity is associated with Parkinson’s disease. This is good news because drugs that destroy a protein’s activity are often easier to engineer than drugs that need to restore activity.

The road to bringing a new, so called “first in class”, drug to a complex disease is itself complex. Missteps along the road to development can cost years of time and I have yet to meet a person with Parkinson’s disease that wants development to happen more slowly. First things first for LRRK2- it is crucial to establish how safe inhibiting LRRK2 is in people, and how much LRRK2 can be inhibited without introducing undesirable effects. Second, the most effective drugs will need to prove their effect in Parkinson’s disease patients that are most likely to benefit from blocking LRRK2. This is going to be a group of Parkinson’s disease patients with known LRRK2 mutations. The Michael J. Fox foundation is assembling the first groups of people together to be tested for LRRK2 mutations through an effort called PPMI, and more information can be found on their website. Finally, after these hurdles, the best drugs that inhibit LRRK2 can be tested in larger Parkinson’s disease populations to see who might benefit, and what kind of benefit, can be expected.

We are close to bringing these innovative approaches and ideas to fruition. As much now as ever, the support of people affected by Parkinson’s disease will make the difference.


Andrew B. West, PhD presented at the First World Parkinson Congress in 2006 and Fourth World Parkinson Congress in 2016. He is an Assosiate Professor of Neurology and Neurobiology at the Center for Neurodegeneration and Experimental Therapeutics at the University of Alabama at Birmingham. 

Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®