ROCKbusting Huntington’s and Probing Parkinson’s
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At the Society for Neuroscience (SfN) conference last held in November 2018 in San Diego, a truly frightening number of posters were presented over nine sessions. The summary document for one of these sessions is 1400 pages long. Whilst attempting to explore all these posters before Neuroscience 2019 begins in Chicago in October would be a rather painful proposition, singling out some of the innovative research in this library of science is far easier, and here we highlight some posters shared by Charles River Laboratories.
The ROCK-y Road to Treating Huntington’s Disease
Huntington’s disease (HD), a dominantly inherited and fatal neurodegenerative disease, is an example of a neurological disorder with an obvious cause (an elongated series of CAG repeats in the gene huntingtin) that has nonetheless proved stubbornly resistant to treatment. In one of several posters in collaboration with CHDI at SfN, Charles River highlighted their joint research towards developing an inhibitor of Rho-kinases (ROCKs), effector proteins that are overexpressed in HD. Blocking ROCK pathways have been shown to promote neuronal survival and reduce protein aggregation in HD cell models, so finding a ROCK inhibitor that can selectively target these pathways whilst also penetrating into the central nervous system has been a priority in the field.
Using literature-based information on known ROCK inhibitors and structure-based drug discovery methods Charles River conducted lead optimization activities to identify a potential proof-of-concept (PoC) candidate, CHDI-00580985, that met the goals of being potent, selective and brain-penetrant. This PoC molecule will be tested in Charles River’s HTT Q175DN KI mouse model to assess any potential therapeutic benefit of inhibiting ROCK and to get some idea of clinical potential.
Pneumocytes and Parkinson’s
Parkinson’s disease (PD) affects more than ten million people worldwide with long-term neurodegeneration that results in motor problems and dementia. At SfN, Charles River’s PD research was detailed over a host of posters. These included a pair of posters in collaboration with the Michael J. Fox Foundation, which, with over $800 million dollars of research funded, is the largest non-profit funder of PD research. These posters investigated the effects of chronic treatment of various mouse models of PD with molecules called leucine-rich repeat kinase 2 (LRRK2) inhibitors. Mutations in LRRK2 proteins boost kinase activity and are implicated in the spread of PD. In their posters, Charles River investigated the action of a LRRK2 inhibitor called PF-360. In one study, researchers explored the oft-noted side effects on lung cells called pneumocytes that can result from treatment with LRRK2 inhibitors. Using both mouse and rat models, researchers investigated PF-360’s effects over a range of doses. They found no changes to the lung cells of rats but noted a modest increase in enlarged type II pneumocytes in AAV-A53T-C57BL6/J and G2019S mouse models.
Moving past side effects, the same team then analyzed how PF-360 affected the parkinsonian traits of these mouse models. Over a battery of tests, where motor, immunological and neurochemical phenotypes were analyzed, researchers were unable to note a robust improvement with PF-360 administration. Whilst, for example, younger G2019S mice had improved hindlimb protraction and retraction after 10 mg/kg of PF-360 was administrated, there was little consistency between doses or between different motor measures.
These studies highlight the innovative work being done using mouse models of PD, but also point to the difficulty of comparison between models and the further research that must be done to develop reliable and robust models that can lead to clinical outcomes.
Take a look through all Charles River's posters from SfN here.