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A multidisciplinary team of scientists led by Carlo Ballatore, Ph.D., of the University of California, San Diego, and Kurt Brunden, Ph.D., of the University of Pennsylvania, has received a $6.9 million grant from the National Institute on Aging (NIA) to prepare a potential disease-modifying treatment for Alzheimer’s disease for future clinical trials. In a recently published study of 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, 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) before human testing can begin. 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 a devastating disease for which there are very few treatment options. We are therefore eager to advance CNDR-51997 through the drug development process. This compound was designed to address tau-mediated neurodegeneration and our preclinical data suggest that it may be beneficial for the treatment of Alzheimer’s disease and related dementias.

Carlo Ballatore, Ph.D., professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego

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 therapies for Alzheimer’s disease, lecanemab (Leqembi™) and donanemab (Kisunla™), target amyloid beta deposits in the brain. It should be noted that there are currently no approved therapies that target pathological tau. In mice, researchers found that CNDR-51997 was able to reduce both amyloid beta plaques and tau pathology in the brain.

In addition to Alzheimer’s disease, there are several other diseases characterized by tau pathology, such as frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, traumatic brain injury, and chronic traumatic encephalopathy (CTE). The researchers believe that their compound could be a future treatment not only for Alzheimer’s disease, but also for other related diseases, collectively known as tauopathies.

“Our findings that CNDR-51997 reduces both Aβ plaques and tau inclusions in mouse models suggest that the compound holds great promise for Alzheimer’s disease. However, there is also a large unmet need for disease-modifying drugs for other tauopathies,” said Brunden, a research professor in the Perelman School of Medicine and director of drug discovery in Penn’s Center for Neurodegenerative Disease Research. “CNDR-51997’s potential to treat tau-related diseases beyond Alzheimer’s disease is another important aspect of its therapeutic promise.”

One of the functions of tau is to stabilize microtubules, dynamic tubular 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 involved in brain function.

In Alzheimer’s disease and other tauopathies, tau protein detaches 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, reducing both Aβ and tau pathologies.

“This is a unique compound with exciting properties, and Dr. Brunden and I are grateful to the NIA for its continued support and for the opportunity to further develop this compound through IND-capable studies, which, if successful, will lead to an IND submission,” Ballatore said.