I018 TT-P34: a novel first-in-class peptide drug for treatment of Huntington’s Disease

<h3></h3> One key hallmark in HD is the dysfunction in the cortico-striatal BDNF-signaling, which leads to loss of CREB activity and ultimately striatal degeneration. Reduced activity of CREB over time leads to loss of proper mitochondrial function, lysosomal function and synaptic integrity, key factors driving the disease progression. TT-P34 is a novel cyclic peptide drug developed by Teitur Trophics. The peptide induces activation of transcription factor CREB to increase both mitochondrial and lysosomal biogenesis and neurotrophic support, evident from studies in several models of neurodegeneration. Here, we treated the zQ175 mouse model over a 9-months period and evaluated a variety of motor functions and performed home-cage analysis as a measure of quality of life. We further investigated the molecular effects of TT-P34 on the striatum of zQ175 mice using unbiased proteomics and metabolomics to correlate behavioral readout with changes in the proteome. Treatment with TT-P34 led to a strong reversal of the HD phenotype measured across 12 behavioral outputs in home-cage analysis in addition to significant improvement in motor-coordination in the transverse beam-test. Proteomics and metabolomics of the striatum revealed extensive protection and upregulation of mitochondrial and synaptic proteins of both dopaminergic, GABAergic, and glutamatergic synapses, as well as increased dopamine and GABA levels, demonstrating that TT-P34 drives key cellular pathways affected in HD, resulting in synaptic resilience and disease modification, validating TT-P34 as a novel and first-in-class drug for HD and potentially other neurodegenerative diseases. Teitur aims to bring TT-P34 it into clinical Phase 1 in Q2 2025.