A team from the University of Barcelona has designed and validated in animal models a compound with a pioneering mechanism of action for the treatment of Alzheimer’s disease.
Unlike current drugs, which mainly remove beta-amyloid plaques that accumulate in the brain, this new experimental drug reprogrammes the neuronal epigenome by correcting alterations in gene expression that contribute to the progression of the disease. The results of the study, published in Molecular Therapy, open the door to an epigenetic-based therapeutic strategy to fight Alzheimer’s disease.
“The compound FLAV-27 represents an innovative and promising approach to Alzheimer’s disease, with the potential to modify the disease process, as it acts not only on its symptoms or a single pathological biomarker, but directly on its underlying molecular mechanisms,” said Aina Bellver, a researcher at the UB Institute of Neurosciences (UBneuro) and first author of the paper.
The study was led by Christian Griñán and Mercè Pallàs, from the Faculty of Pharmacy and Food Sciences, with the participation of researchers from UBneuro and the CIBER Area for Neurodegenerative Diseases (CIBERNED), as well as the UB Institute of Biomedicine (IBUB), the Institute of Nutrition and Food Safety (INSA-UB), the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and other national and international institutions.
The drugs currently approved to treat Alzheimer’s, such as lecanemab and donanemab, are monoclonal antibodies that work by removing beta-amyloid protein plaques from the brain.
“Although they represent a breakthrough, their efficacy is limited, as they only slow cognitive decline by 27% to 35%, have several side effects and only address the part of the pathology caused by beta-amyloid accumulation,” the researchers said.
FLAV-27 works in a different way: it is the first inhibitor in its class to affect the G9a enzyme, which is essential in the epigenetic regulation of the brain because it helps to silence genes that are fundamental for neuronal development, synaptic plasticity and memory consolidation.
To inhibit G9a, the new drug prevents access by the natural molecule S-adenosylmethionine (SAM), which the enzyme needs to modify DNA. It thus slows down the epigenetic dysregulation, characteristic of Alzheimer’s disease, and allows neurons to regain normal function.
The study shows that inhibiting G9a with FLAV-27 not only reduces classic pathological markers, such as beta-amyloid protein and phosphorylated tau, which accumulate in the brains of people with Alzheimer’s disease, but also restores cognitive function, social behaviour and the structure of neuronal synapses in various models: from in vitro assays, through the worm C. elegans — in which it improves mobility, life expectancy and mitochondrial respiration — to murine models of late-onset and early-onset Alzheimer’s disease.
“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.
According to the authors, these results confirm that epigenetic dysregulation — changes in the chemical mechanisms that determine which genes are activated or not without altering the DNA sequence — is not just a side effect of Alzheimer’s disease, but an active and controllable mechanism that links the main pathological features of the disease, such as beta-amyloid and tau proteins, neuroinflammation and synaptic dysfunction, through a common epigenetic axis.
This opens the door to a new category of therapies: epigenetic disease-modifying treatments, which could complement or even replace current strategies, which are based exclusively on the elimination of beta-amyloid.
A key finding that adds to the translational value of this treatment is the identification of a biomarker that can be measured in both the brain and blood plasma of patients. The team found that the epigenetic marker H3K9me2, the SMOC1 protein and the p-tau181 molecule are significantly elevated and that their blood levels correlate directly with symptoms such as tau protein accumulation, neuroinflammation and the degree of cognitive impairment. When FLAV-27 is administered in animal models, these indicators return to normal levels, in parallel with cognitive recovery.
The availability of these peripheral bioindicators is one of the key aspects that distinguishes FLAV-27 from other drugs in development.
“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.
Despite these promising results, FLAV-27 still needs to pass further stages before clinical trials can begin in humans. Currently in the advanced preclinical phase, the next steps include regulatory toxicology studies in at least two animal species, obtaining the pharmaceutical form, and preparing the regulatory dossier to apply for clinical trial authorisation from the relevant agencies, a process that will take years.
The new phase will be led by Flavii Therapeutics, a spin-off from the UB founded in 2025 and holder of the exclusive licence for FLAV-27. The company will take on the preclinical and clinical development of the drug, as well as the management of intellectual property and fundraising, with the aim of converting the knowledge generated at the UB into new therapies for central nervous system diseases such as Alzheimer’s.