Researchers from the University of Barcelona announced on Mar. 19 the development and validation in animal models of a new compound with a novel mechanism for treating Alzheimer's disease. Unlike existing drugs that focus on removing beta-amyloid plaques from the brain, this experimental drug reprograms the neuronal epigenome by correcting gene expression changes linked to disease progression.
This approach is significant because current treatments, such as lecanemab and donanemab, are monoclonal antibodies that only slow cognitive decline by 27% to 35%, have several side effects, and address only part of the pathology caused by beta-amyloid accumulation, according to the researchers. The study's results were published in Molecular Therapy.
The new compound, FLAV-27, is described as the first inhibitor in its class to target the G9a enzyme. This enzyme plays a key role in silencing genes essential for neuronal development and memory consolidation. By blocking access to S-adenosylmethionine (SAM), which G9a needs to modify DNA, FLAV-27 slows down epigenetic dysregulation characteristic of Alzheimer's and helps neurons regain normal function.
In various models—including cell cultures, C. elegans worms, and mouse models—FLAV-27 not only reduced classic pathological markers like beta-amyloid protein and phosphorylated tau but also restored cognitive function and social behavior. "In these models, there is evidence of improved short- and long-term memory, spatial memory and sociability, which demonstrates not only an effect on molecular markers, but also functional cognitive recovery," the researchers said.
The team also identified biomarkers measurable in both brain tissue and blood plasma that correlate with symptoms such as tau accumulation and neuroinflammation. Administration of FLAV-27 normalized these indicators alongside cognitive improvements. "It has important implications for future clinical trials, as it will allow the selection of suitable patients with a simple blood test, monitoring of treatment and demonstration that the drug actually modifies its therapeutic target," the authors said.
Although promising, FLAV-27 remains in advanced preclinical testing stages. Further regulatory toxicology studies are required before human clinical trials can begin—a process expected to take years. Flavii Therapeutics, a spin-off company founded in 2025 by UB researchers holding exclusive rights to FLAV-27, will lead further development efforts.
