New compound shows promise in Alzheimer’s preclinical models

A multidisciplinary team of scientists led by Kurt Brunden, Ph.D., at the University of Pennsylvania’s Perelman School of Medicine, and Carlo Ballatore, Ph.D., at the University of California San Diego, has awarded a grant. $6.9 million received from the National Institute on Aging (NIA) will prepare a potential disease-modifying treatment for Alzheimer’s disease for future clinical trials. In a recently published study on the new compound, called CNDR-51997, the team found that 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, which 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 start 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 trials.

Alzheimer’s disease is characterized by abnormal deposits of two types of proteins in the brain: amyloid beta (Aβ) and tau. The only currently available disease-modifying treatments for Alzheimer’s disease, 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 could reduce both Aβ plaques and tau pathology in the brain.

In addition to Alzheimer’s disease, 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 their compound could be a future treatment not only for Alzheimer’s disease, 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 significant promise for Alzheimer’s disease. However, there is also a large 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 disease is another important aspect of its therapeutic promise.”

Kurt Brunden, Perelman School of Medicine, University of Pennsylvania

One of tau’s functions 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 components are distributed to different parts of the long axonal extensions involved in brain function.

In Alzheimer’s disease and other tauopathies, tau becomes detached from microtubules, causing them to become disorganized. This leads to axonal transport deficits and neuronal loss. In preclinical studies, the novel compound CNDR-51997 was able to correct these imbalances, ultimately reducing both Aβ and tau pathologies.

“Alzheimer’s disease is a devastating disease with very few treatment options, so we are eager to advance CNDR-51997 in the drug development process,” said Ballatore, professor at the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. designed to combat tau-mediated neurodegeneration and our preclinical data suggest it could be beneficial for the treatment of Alzheimer’s disease and related dementias.”