Welcome to the Longo Lab

We elucidate mechanisms underlying neurodegenerative disorders, including Alzheimer’s disease and other neurological conditions, and use these discoveries to develop and characterize small molecule therapeutic strategies that promote resilience to neurodegeneration. Promotion of resilience is currently a major priority in the field of neuro therapeutics. We also develop translational biomarkers to assess therapeutic target engagement and potential treatment efficacy.

Neurotrophin receptors (p75, TrkA, TrkB, TrkC) are expressed by neurons and glial cells and their intracellular signaling networks have a remarkable overlap with degenerative signaling networks triggered in the setting of neurodegenerative diseases. Modulation of these receptors provides a powerful opportunity to counteract a broad spectrum of neurodegenerative disease mechanisms including those underlying accumulation of toxic proteins, synaptic resilience, synaptic function, and glial activity. We pioneered the development of small molecules that can activate or modulate neurotrophin receptors. These small molecules drive unique biological effects that counteract disease mechanisms observed in a variety of neurodegenerative disease models including in vitro and in vivo models of tauopathies, and Alzheimer’s, Huntington’s, and Parkinson’s diseases. One of these molecules, the p75 neurotrophin receptor ligand LM11A-31, has progressed through two human phase 1 safety and pharmacokinetic trials and a phase 2a Alzheimer’s disease trial. We have executed the rare, full translational spectrum, from identifying novel disease mechanisms, to developing molecules to target them, validating these molecules in preclinical models, and advancing one to first-in-human safety studies and first-in-class testing with positive outcomes in neurodegenerative disease subjects. 

Ongoing projects focus on evaluating potential therapeutic targets and drug candidates using diverse approaches, including advanced applications of preclinical disease models, omics, bioinformatics, electrophysiology, in vivo calcium imaging, and standard molecular biology and biochemical techniques. We are also developing fluid and imaging biomarkers to support these efforts.