Next-Generation alzheImer'S Therapeutics - Trial NCT06372587

Timeline & Enrollment

Primary Outcome

To use genetically encoded engineered proteins to obtain an inducible control of their activity in living human neurons preventing dendritic spines loss,To leverage genetically encoded engineered proteins to prevent alterations in the morphology of dendritic spines in living human neurons,To use genetically encoded engineered proteins to obtain an inducible control of their activity in living human neurons promoting functional synaptic plasticity,To use genetically encoded engineered proteins to obtain evaluate neuronal excitability in living human neurons

Summary

Is this the right time to use next-generation approaches in Alzheimer's disease (AD)? In
 recent years, several large clinical trials testing treatments for AD have failed, putting
 the entire field on a reset. AD drug trials have almost exclusively sought to use antibodies
 targeted toward misfolded amyloid and tau proteins. Of note, although these approaches have
 failed, they were designed to cover both familial and sporadic forms of AD. On the other
 hand, the failure in developing new effective drugs is attributed to, but not limited to, the
 highly heterogeneous nature of AD with multiple underlying hypotheses and multifactorial
 pathology. The idea underlying this project is based on the assumption that learning and
 memory disorders can arise when the connections between neurons do not change appropriately
 in response to experience. Thus, by intervening on the core mechanisms of the cellular
 correlate of learning and memory, i.e., synaptic plasticity, the investigators expect to
 preserve some of the essential brain functions in AD. By overcoming the limits of traditional
 AD therapeutic approaches, the investigators will use genetically encoded engineered proteins
 (GEEPs), which the investigators developed and tested in vitro and in murine models, to
 control their activity in living human neurons boosting synaptic plasticity. Indeed,
 outstanding and relevant progress in understanding synaptic physiology empowers the
 possibility to prevent or limit brain disease like never before. The investigators designed
 GEEPs to address some of the leading causes of synaptic plasticity failures documented in AD.
 Thus, GEEPs will be tested in human induced pluripotent stem cells (hiPSCs)-derived living
 neurons obtained from reprogrammed peripheral tissues of participants with Alzheimer's
 diseases. hiPSCs will be obtained from fibroblast-derived from a skin biopsy of participants
 with AD and controls performed in local anesthesia using a 4 mm punch. The findings will
 provide the first preclinical study on the effect of genetically engineered proteins to
 control essential pathways implicated in synaptic plasticity on AD-related cognitive decline.

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