Dr. Stephen Strittmatter, Yale University: Repositioning an experimental cancer drug to target Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia, a group of disorders that cause progressive loss of memory and other mental processes. An estimated 5 million Americans have Alzheimer’s disease, which causes clumps of amyloid beta protein to build up in the brain, and these protein clusters damage and ultimately kill brain cells (neurons). Alzheimer’s disease also leads to loss of synapses, which are the spaces between neurons, through which the cells talk to each other and form memories. Current Alzheimer’s drug therapies can only ease symptoms without stopping disease progression. New treatments are needed that can halt the condition by targeting its underlying mechanisms.

Through NCATS’ New Therapeutic Uses program, Yale neurobiology researcher and neurologist Stephen Strittmatter, M.D., Ph.D., and his colleagues obtained saracatinib (AZD0530), which had originally been studied for the treatment of cancer. Strittmatter and his team knew from previous studies that a protein called Fyn kinase plays a central role in how amyloid beta clusters damage brain cells. Saracatinib targets the same Fyn protein and had already been tested for safety in human clinical studies.

The Yale team conducted an animal study in which the experimental drug was dosed to mice with Alzheimer’s-like symptoms, such as memory loss and age-related build-up of abnormal amyloid beta clusters, modelling the development of the disease in humans. After four weeks, the Alzheimer’s mice showed complete reversal of spatial learning and memory loss. When the scientists examined the brains of the mice, they found that the characteristic synapse loss had been fully restored, providing a biological explanation for the memory improvement. The treatment also reduced several other Alzheimer’s-related biochemical changes in the mice and did not appear to be toxic. This data was reported in Annals of Neurology.

Already, the Yale scientists have completed a successful Phase 1b safety trial in humans with Alzheimer’s disease, the results of which were published in Alzheimer's Research & Therapy. The team is currently enrolling more participants in a larger, multisite Phase 2a trial to assess safety, tolerability and effectiveness of Saracatinib in Alzheimer’s patients. A total of 152 participants will receive Saracatinib or placebo for one year, and the researchers expect to have final results within two years.