The Michael J. Fox Foundation, an organization devoted to supporting the diagnosis and treatment of Parkinson’s disease, has expanded its collaboration with contract research organization, Charles River Laboratories. The two are working together to investigate mutations in the LRRK2 gene, which are the greatest known genetic causes of Parkinson’s disease (PD). The team seeks to develop a mouse model of PD to understand the effects of LRRK2 inhibitors as a novel therapeutic strategy in preventing the progression of the disease. Experts from Charles River Laboratories (CRL) spoke to Bioscience Technology and answered a few questions about the partnership and research goals.
David Fischer, Ph.D., is Executive Director of Biology and Drug Metabolism and Pharmacokinetics Discovery and Robert Hodgson, Ph.D., is Director of Science, Research and Discovery, Discovery Site Operations, at Charles River Laboratories.
Why did The Michael J. Fox Foundation (MJFF) decide to partner with a contract research organization (CRO)? Are these kinds of partnerships becoming more common, and if so why?
We have the ability to provide MJFF with a large suite of assays that could be used to fully characterize a novel animal model and to help identify a therapeutic window for LRRK2 inhibitors as a class. As a CRO, we are able to evaluate compounds from multiple pharmaceutical companies working on this target without any bias, providing a fully objective readout of their molecules. And on the in vitro side, our chemistry expertise and strong project management have proven useful on a separate MJFF-led project to develop a positron emission tomography (PET) radiotracer to visualize the distribution of alpha-synuclein aggregates found in pathological conditions characterized by Lewy bodies, such as Parkinson's disease. Relationships that involve multiple companies to form a pre-competitive consortium have become more common, and MJFF is perhaps the best example in our industry of an organization that breaks down barriers that have historically impeded collaboration.
How will this new work being carried out with the MJFF build on previous research?
CRL previously worked with other clients to develop selective LRRK2 inhibitors that cross the blood-brain-barrier (J Med Chem 55 (22): 9416-9433). We are also able to work with a high number of PD-relevant endpoints in rodents, making it an ideal CRO with whom to partner in order to achieve assessments of novel animal models, compound effectiveness and validation of novel biomarker strategies. Finally, we have the ability to provide data-rich analyses of any of these approaches by tying together these multiple readouts in the same animal.
How significant a role do small-molecule LRRK2 inhibitors play in Parkinson’s drug development? And what makes them such promising drug targets?
For neurodegenerative diseases, it is challenging to find novel targets that have strong human validation. LRRK2 is an exception. Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Although the majority of Parkinson’s disease is not caused by single gene mutations, targeting the same pathway in patients with sporadic Parkinson’s disease as well as in LRRK2 carriers is thought to be a potential disease-modifying approach.
What are the biggest challenges researchers face working with LRRK2 inhibitors and the enzyme they target?
A major challenge to developing LRRK2 inhibitors is making sure they cross the blood-brain-barrier as PD is a disorder of the central nervous system. In addition, pharmacodynamic biomarkers are needed to guide dose-efficacy relationship predictions. Genetic animal models involving LRRK2 over-expression have not historically generated a robust phenotype, which makes pharmacodynamic and pre-clinical efficacy studies difficult. This is why CRL works closely with The Michael J. Fox Foundation to improve on existing animal models that can drive forward research to discover new treatments or cures for PD.
What is it about Charles River’s in vitro biology expertise that makes you well-suited for developing a screening assay for protein aggregation?
CRL’s leadership in high-throughput screening, combined with CRL’s expertise in human primary cells and stem cells allows us to develop novel screening assays for alpha-synuclein in vitro biology.
Can you describe the scope and progress of other research projects with the MJFF, particularly the development of an a-synuclein imaging agent?
Since 2011, we have been part of an MJFF-led consortium to discover and develop a novel PET imaging agent for Lewy bodies, the neuropathological hallmark of Parkinson’s disease. CRL works together with a number of academic and industry partners that contribute unique reagents and brain material to help us optimize the molecules towards these highly needed imaging agents.
http://www.biosciencetechnology.com/news/2016/02/michael-j-fox-foundation-partners-charles-river-laboratories-parkinsons-research
No comments:
Post a Comment