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Experimental Drug Shown to Prevent Memory Loss

Neurons illustration

Neurons (Laura Struzyna, University of Pennsylvania, NIH.gov)

10 Sept. 2019. A drug candidate designed to compensate for damage to brain cells from toxic proteins prevented nerve cell damage and memory loss in lab mice. Test results assessing the drug code-named BPN14770 made by Tetra Therapeutics appear in the 5 September issue of the Journal of Pharmacology and Experimental Therapeutics.

The study is a collaboration between Tetra Therapeutics, a biotechnology company in Grand Rapids, Michigan, and researchers from the pharmacy school at University at Buffalo in New York. Tetra Therapeutics is developing BPN14770 to protect against further damage to neurons, or nerve cells in the brain from the build-up of the toxic proteins amyloid-beta and tau that form plaques on neurons. Unlike other drugs that try to address the toxic proteins directly, BPN14770 blocks another protein unleashed during this process, PDE4D, short for phosphodiesterase-4D.

PDE4D is an inhibitor of cyclic adenosine monophosphate, or cyclic AMP, a signaling molecule that regulates immune cell functions, including inflammation. In the brain, cyclic AMP helps form and sustain memories by supporting signaling functions of nerve cells in the brain. The researchers, led by Buffalo research professor Ying Xu and pharmacy school dean James O’Donnell, cite earlier studies showing that toxic proteins can build up on nerve cells in as many as 30 percent of older individuals without forming symptoms of dementia.

“Such observations,” says Xu in a university statement, “imply that Alzheimer’s pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels.” The team hypothesized that in this process, cyclic AMP compensates for initial nerve cell damage by helping form new nerve cell connections and preventing further harm. But PDE4D blocks cyclic AMP from working, thus inhibiting the actions of PDE4D with BPN14770 can allow cyclic AMP to function properly.

To assess these assumptions, the researchers tested BPN14770 in lab mice bred with human genes expressing PDE4D proteins. The team injected amyloid-beta proteins into the hippocampus region of the mice brains, the part of the brain associated with learning and memories, which caused damage to dendrites, extensions of nerve cells for signaling. In mice given BPN14770, however, that damage is prevented, with the higher the dose, the less damage that occurs. Further tests with mice in water-mazes and Y-mazes also show mice given BPN14770 are better able to remember escape routes through the mazes.

“Our new research suggests,” Xu notes, “that BPN14770 may be capable of activating multiple biological mechanisms that protect the brain from memory deficits, neuronal damage, and biochemical impairments.”

Tetra Therapeutics is already testing BPN14770 in a mid-stage clinical trial with patients having mild to moderate Alzheimer’s disease. Mark Gurney, the company’s CEO and a co-author of the paper says, “The role of PDE4D in modulating brain pathways involved in memory formation and cognition, and the ability of our PDE4D inhibitor to selectively enhance this process, has been well studied.” He adds that the new findings, “suggest a second protective mechanism of action for BPN14770 against the progressive neurological damage associated with Alzheimer’s disease.”

BPN14770 is also being developed as a treatment for fragile X syndrome, a genetic disorder affecting males more severely than females, where nerve signaling functions in the brain are impaired and do not mature. Fragile X syndrome causes cognitive impairment and delays intellectual development in children. Tetra Therapeutics is testing BPN14770 in a clinical trial of adult males with fragile X syndrome.

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