A compound that blocks the activity of so-called HDAC enzymes in the brain improved learning in mouse models of Alzheimer’s disease, according to data that Regenacy Pharmaceuticals presented at the recent 2017 Alzheimer’s Association International Conference (AAIC) July 16-20 in London.
Regenacy’s RCY-1305 blocks the enzymes HDAC1 and HDAC2, which are part of the mechanisms that control how genes are activated. Researchers believe that abnormal processes involving the enzymes might contribute to cognitive decline.
Matt Jarpe, Regenacy’s vice president of research and development, presented the study titled “A Highly Brain Penetrant HDAC1,2 Inhibitor (RCY-1305) Improves Cognitive Function in Mouse Models of Alzheimer’s Disease,” which was part of a session discussing new therapies.
“We found that after two days of oral dosing, RCY-1305 successfully resulted in HDAC1,2 inhibition in the brains of mice and increased the transcription of genes associated with synaptic plasticity,” Jarpe said in a press release.
“Both normal and cognitively impaired mice demonstrated improved performance of special learning tasks after four weeks of dosing,” Jarpe said. “These results suggest that HDAC1,2 inhibition is a promising area of research to develop potential therapeutics for [Alzheimer’s disease] and other diseases in which cognition is impaired.”
Currently available drugs that block HDAC enzymes do so in a rather unspecific manner. Since there are 18 known HDAC enzymes, blocking these in healthy cells may cause a range of side effects, including gut problems, reduced platelet numbers, and bleeding risk. They are also known to trigger fatigue and have the potential to cause severe heart toxicity.
By targeting only the 1 and 2 types of the enzymes, the company hopes to reduce the side effects linked to less specific compounds. In addition, RCY-1305 enters the brain at a good rate — a crucial feature of a drug that targets a brain disease such as Alzheimer’s.
HDACs act by removing chemical acetyl groups from DNA. Such chemical flags are used to control how DNA is folded in the cell, which in turn impacts how genes can be accessed by the protein-making machinery.
An earlier study found that the APOE4 Alzheimer’s risk gene impacts disease risk by reducing the number of synapses in the brain — a task achieved with the help of activated HDAC enzymes.
Others have also noted that HDAC blockers, originally developed as a cancer treatment, improve memory and learning in animals.