LRRK2 and Parkinson's Disease
What is LRRK2
Discovered in 2004, leucine-rich repeat kinase 2 (LRRK2) is the greatest known genetic contributor to Parkinsonís disease.
By and large, Parkinsonís disease has not been considered to be a genetic disease. The majority of cases are called idiopathic, which simply means that we don't know what caused the disease. In fact, only about 10 percent of Parkinsonís disease cases so far have been linked to a genetic cause. Mutations in the LRRK2 gene are the most common cause of Parkinsonís disease in this relatively small group, representing one to two percent of total Parkinson's cases.
However, for people of two particular ethnic backgrounds ó Ashkenazi Jewish and North African Arab Berbers ó mutations in LRRK2 account for a much greater number of Parkinsonís disease cases than in the general population. While estimates vary, it is believed that changes in LRRK2 (predominantly the mutation scientists know as G2019S) account for 15 to 20 percent of Parkinsonís disease cases in Ashkenazi Jews and about 40 percent of cases in North African Arab Berbers. Other genetic changes in LRRK2 that increase the risk of Parkinsonís disease have been found in additional populations, such as in Asians of Chinese descent. It remains an active area of investigation to find all the genetic changes in LRRK2 that may lead to Parkinsonís disease.
Genetic targets allow us to study important mechanisms underlying disease onset and progression. By studying LRRK2, we can speed progress toward treatments that would benefit everyone with the disease, not just those with genetic mutations.
How is The Michael J. Fox Foundation targeting LRRK2?
The Michael J. Fox Foundation is pioneering an innovative approach to LRRK2 in an effort to streamline and orchestrate drug development around the gene. Our goal is to bring research groups together early on ó sharing resources, troubleshooting common problems and identifying best resources ó to speed collective efforts to move LRRK2 toward practical therapeutic relevance for patients.
The Foundation is funding a large LRRK2 Consortium to test critical hypotheses about both normal and pathological LRRK2. This collaborative network of more than 30 investigator teams will help researchers understand LRRK2's structure and function in order to identify drug candidates that can modify its activity in the body and the brain.
We are concurrently assembling groups of people with LRRK2 mutations and their family members all over the world who can be studied by doctors, so that the field will better understand the nature of Parkinson's disease clinical features in the presence of LRRK2. By studying people who carry the LRRK2 mutation and do not have Parkinsonís disease, we may also learn about the very first signs of disease that could be used to detect Parkinsonís disease even earlier than we can today. This will set the stage for more efficient clinical trials once candidate drugs are found, and for determining how to design a drug for LRRK2 parkinsonism that will also help people who do not have the mutation.
At the same time, the Foundation is leading the development and distribution of critical research tools, such as pre-clinical models and laboratory reagents, which remove hurdles for investigators to effectively study LRRK2 and test new hypotheses about how to exploit its weaknesses for patients' benefit. Due to competition within the research community to understand LRRK2, as well as restrictive patents, there is traditionally limited sharing of tools and resources. The Foundation has created a new model, developing many of the tools in order to make them more freely available to the researchers who want them with fewer restrictions.
The Foundation also plays a convening role to ensure that the pharmaceutical industry's expertise is being leveraged in the pursuit of LRRK2-based therapeutics. Industry's perspective is critical if we are to efficiently make drugs for LRRK2. For example, mounting a clinical trial to test a LRRK2-based therapeutic would require both the therapeutic itself and other resources, such as imaging markers that can indicate the effectiveness of the candidate drug. The LRRK2 Industry Advisory Group is collaborating with the Foundation in a precompetitive space to discuss how to best create and share these kinds of resources in moving forward to develop LRRK2-targeted drugs.
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