PRECLINICAL VALIDATION OF A BDNF ALLOSTERIC MODULATOR IN A HUMAN STEM CELL-DERIVED NEURAL MODEL: IMPLICATIONS FOR HUNTINGTON'S DISEASE

Brain-derived neurotrophic factor (BDNF), the major neurotrophin in the adult brain, plays a central role in neuronal survival, axonal growth, synaptic plasticity, and circuit maintenance. BDNF exerts its effects primarily through activation of the TrkB receptor, engaging downstream MAPK/ERK, PI3K/Akt, and PLCγ signaling pathways. Impaired BDNF availability and disrupted TrkB signaling are hallmark features of several neurodegenerative disorders, including Huntington’s disease (HD), where mutant huntingtin interferes with BDNF production, transport, and synaptic delivery.
To overcome BDNF-TrkB deficit, we identified and developed LIT_TB001, a small-molecule positive allosteric modulator (PAM) of the TrkB receptor. By selectively enhancing endogenous BDNF-TrkB interactions, LIT_TB001 amplifies physiological signaling without bypassing activity-dependent regulation. In rodent HD models, LIT_TB001 robustly enhances TrkB phosphorylation, activates pro-survival signaling cascades, and promotes neuronal growth and survival, demonstrating significant neuroprotective efficacy both in vitro and in vivo.
To strengthen translational relevance, we validated TrkB target engagement in a human context using hiPSC-derived glutamatergic neurons. LIT_TB001 effectively potentiates BDNF-induced TrkB signaling in human neurons, reproducing key molecular effects observed in animal models. Building on these results, we are now developing a human HD-on-chip platform combining hiPSC-derived glutamatergic and GABAergic neurons in a microfluidic co-culture system that recapitulates key features of corticostriatal organization and connectivity.
This humanized HD-on-chip model provides a physiologically relevant framework to investigate BDNF/TrkB modulation in disease-specific circuits and represents a critical step toward bridging preclinical studies and future clinical translation in Huntington’s disease.