Galenea, a Cambridge, Mass.-based company focused on synaptic transmission drug discovery, and CHDI Foundation, a not-for-profit, biomedical research organization focused on Huntington’s disease (HD), have extended and expanded their collaboration to further characterize the synaptic dysfunction apparent in HD utilizing Galenea’s proprietary platform.
Galenea’s synaptic transmission drug discovery platform is providing significant new insights into the disease mechanism, and the collaboration will now focus on extending these findings in order to specifically target this mechanism to discover novel therapies for HD.
“As we and CHDI had anticipated, our platform is well suited to unraveling the synaptic dysfunction in HD and, ultimately, the discovery of synaptic-based therapeutics,” said David Gerber, vice president of CNS research, Galenea. “The findings in the first phase of work were very compelling, and we see the potential for completely new approaches to this devastating disease.”
The first phase of the collaboration led to the discovery of alterations of synaptic vesicle dynamics in cortical synapses from HD cellular models and in cortical EEG measures in HD animal models.
“The collaboration has yielded new insights into the cellular causes of synaptic dysfunction in HD that are not accessible by other means,” said Ramee Lee, director of early discovery initiative, CHDI. “We now see changes in synaptic function in multiple models of HD, using both MANTRA assays and rodent EEG readouts, and these changes occur prior to the onset of synaptic loss.”
Dysfunctions in synaptic transmission, the fundamental process by which neurons communicate, play a critical role in many central nervous system diseases, including HD. Mutant huntingtin protein, the causative defect in HD, appears to disrupt normal synaptic function, contributing to the behavioral, cognitive and motor symptoms of this neurodegenerative disorder. Galenea’s platform targets synaptic transmission on multiple levels. The MANTRA (Multiwell Automated Neuro TRansmission Assay) system, a novel high-throughput screening technology, directly monitors synaptic events at the cellular level in primary neuronal cultures.
At the network level, Galenea has developed a state-of-the-art system to establish in vivo electroencephalography (EEG) measures of behaviors in rodent disease models by monitoring brain and behavioral activities in parallel. The collaboration has employed this two-pronged approach to characterize the synaptic defects that occur in HD at both the neuronal and network levels, which may explain some critical features of the disease.
“This second phase of our collaboration with Galenea will focus on understanding whether there is a polyglutamine-length dependency to the observed synaptic alterations and on building a broad HD drug-discovery platform through the application of these novel findings,” said George Yohrling, director of target assessment, CHDI. “By determining the applicability of these synaptic and network changes, we will develop critical in vitro and in vivo screening tools to identify either small molecules or biological pathways that can ameliorate the synaptic effects of mutant huntingtin.”