AΒ PATHOLOGY REDUCTION AND SAFETY VALIDATION OF HE2F4DN-BASED GENE THERAPY FOR ALZHEIMER’S DISEASE​

Alzheimer’s disease (AD) is a global health priority, affecting over 50 million people worldwide. Given the lack of effective treatments, we have developed a multifactorial gene therapy based on hE2F4DN, a mutated form of the human transcription factor E2F4 unable to become phosphorylated by the stress kinase p38MAPK. Neuronal expression of hE2F4DN maintains brain homeostasis in the presence of active p38MAPK, known to be activated at early staged of AD. This strategy is currently licensed by the spin-off Tetraneuron S.L. We have evaluated the disease-modifying potential of AAV.hSyn1.hE2F4DN. This therapeutic vector was intracisternally-administered in homozygous 5xFAD mice at 6 weeks, when these mice are asymptomatic, and 3 months, when they already show memory loss. Our results indicate that hE2F4DN significantly reduces the levels of soluble Aβ monomers and oligomers (oAβ) as well as the average Aβ plaque area in the hippocampus of 6-month-old mice, regardless of the age of administration. Parallel to these findings, we conducted a rigorous safety assessment. We confirmed that hE2F4DN expression does not alter neuronal complexity or morphology in the hippocampus of wild-type mice. Importantly, we validated these findings in human iPSC-derived neurons, providing a crucial translational bridge between murine models and clinical application in humans. This reinforces the safety profile of our molecule across species without compromising neuronal integrity. Collectively, these findings demonstrate that hE2F4DN gene therapy effectively reduces Aβ pathology while maintaining high safety standards. We propose this multifactorial approach as a promising and safe candidate for the treatment of Alzheimer’s disease.