Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

• DOI: 10.1007/s13311-021-01023-8
• Publication Date: 2021-03-30T21:02:21Z
• Authors: Danielle A. Simmons; Brian D. Mills; Robert R. Butler III; Jason Kuan; Tyne L.M. McHugh; Carolyn Akers; James Zhou; Wassim Syriani; Maged Grouban; Michael Zeineh; Frank M. Longo
• Keywords: Male; 0301 basic medicine; 2. Zero hunger; Morpholines; Drug Evaluation, Preclinical; Mice, Transgenic; Neuroimaging; Receptors, Nerve Growth Factor; 3. Good health; Mice; 03 medical and health sciences; Cross-Sectional Studies; Huntington Disease; 0302 clinical medicine; Mice, Inbred CBA; Animals; Original Article; Female; Isoleucine; Biomarkers

Huntington's disease (HD) is caused by an expansion of the CAG repeat in huntingtin gene leading to preferential neurodegeneration striatum. Disease-modifying treatments are not yet available HD patients and their development would be facilitated translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) plasma cytokines have been suggested as onset/progression biomarkers, but ability detect treatment efficacy understudied. This study used R6/2 mouse model assess if structural neuroimaging biofluid assays can response using a prototype small molecule p75NTR ligand LM11A-31, shown previously reduce phenotypes these mice. LM11A-31 alleviated volume reductions multiple brain regions, including striatum, vehicle-treated mice relative wild-types (WTs), assessed with vivo MRI. also normalized changes diffusion tensor (DTI) metrics diminished increases certain cytokine levels, tumor necrosis factor-alpha interleukin-6, Finally, R6/2-vehicle had increased urinary levels extracellular domain (ecd), cleavage product released pro-apoptotic binding that detects progression other neurodegenerative diseases; reduced this increase. These results first show p75NTR-ecd elevated therapeutic effects. data indicate multi-modal MRI may effective biomarkers combinations markers viable powerful option for clinical trials.