This illustration shows tau protein (red) becoming detached from a microtubule (blue). A new compound discovered by researchers at UC San Diego and University of Pennsylvania may be able to treat Alzheimer's disease by normalizing microtubule structure and function.
A multidisciplinary team of scientists led by Kurt Brunden, Ph.D., at the University of Pennsylvania Perelman School of Medicine, and Carlo Ballatore, Ph.D., at University of California San Diego, has been awarded a $6.9 million grant from the National Institute on Aging (NIA) to prepare a potential disease-modifying Alzheimer’s treatment for future clinical trials. In a recently published study about the new compound, called CNDR-51997, the team found it was effective in restoring brain health in mouse models of Alzheimer's disease. CNDR-51997 was identified through a joint drug discovery program at Penn and UC San Diego that was supported by grants from the NIA.
The new grant will help the researchers demonstrate the drug’s safety in formal studies required by the U.S. Food and Drug Administration (FDA) prior to the initiation of human testing. By the end of the three-year grant period, the researchers hope to submit an Investigational New Drug (IND) application to the FDA that, if approved, would allow for Phase 1 clinical studies.
Alzheimer’s disease is characterized by abnormal deposits of two types of protein in the brain: amyloid beta (Aβ) and tau. The only currently available disease-modifying treatments for Alzheimer’s, lecanemab (Leqembi™) and donanemab (Kisunla™), target Aβ deposits in the brain. Notably, there are currently no approved therapies that target pathological tau. In mice, the researchers found that CNDR-51997 was able to reduce both Aβ plaques and tau pathology in the brain.
In addition to Alzheimer’s there are several other diseases characterized by tau pathology, such as traumatic brain injury, chronic traumatic encephalopathy (CTE), frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease. The researchers believe that their compound could not only be a future treatment for Alzheimer’s, but also for these other related diseases, collectively called tauopathies.
“Our findings that CNDR-51997 reduces both Aβ plaques and tau inclusions in mouse models suggest that the compound holds considerable promise for Alzheimer’s disease. However, there is also a great unmet need for disease-modifying drugs for the other tauopathies,” said Brunden, a research professor and director of drug discovery at Penn’s Center for Neurodegenerative Disease Research. “The potential of CNDR-51997 to address tau-related diseases beyond Alzheimer's is another important aspect of its therapeutic promise.”
One of the functions of tau is to stabilize microtubules, dynamic tube-like structures that help give cells their shape. In neurons, microtubules play an important role in axonal transport, a process in which proteins and other cellular constituents are distributed to different parts of the long axonal extensions that are involved in brain function.
In Alzheimer’s disease and other tauopathies, tau becomes detached from microtubules, which causes them to become disorganized. This leads to axonal transport deficits and neuronal loss. In preclinical studies, the new compound CNDR-51997 was able to correct these imbalances, ultimately reducing both Aβ and tau pathologies.
"Alzheimer’s is a devastating disease with very few treatment options, so we are eager to advance CNDR-51997 through the drug development process," said Ballatore, a professor at UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences.” This compound has been designed to combat tau-mediated neurodegeneration and our preclinical data suggest that it could be beneficial for the treatment of Alzheimer's and related dementias.”
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