A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse.
Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine expansion within huntingtin protein. The exact pathological mechanisms determining disease onset and progression remain unclear. However, aggregates of insoluble mutant huntingtin (mhtt), a hallmark of HD, are readily detected within neurons in HD brain. Although aggregated polyglutamines may not be inherently toxic, they constitute a biomarker for mutant huntingtin useful for developing therapeutics. We previously reported that the small molecule, C2-8, inhibits polyglutamine aggregation in cell culture and brain slices and rescues degeneration of photoreceptors in a Drosophila model of HD. In this study, we assessed the therapeutic potential of C2-8 in the R6/2 mouse model of HD, which has been used to provide proof-of-concept data in considering whether to advance therapies to human HD. We show that, at nontoxic doses, C2-8 penetrates the blood-brain barrier and is present in brain at a high concentration. C2-8-treated mice showed improved motor performance and reduced neuronal atrophy and had smaller huntingtin aggregates. There have been no prior drug-like, non-toxic, brain-penetrable aggregation inhibitors to arise from cell-based high-throughput screens for reducing huntingtin aggregation that is efficacious in preclinical in vivo models. C2-8 provides an essential tool to help elucidate mechanisms of neurodegeneration in HD and a therapeutic lead for further optimization and development.
Chopra
Vanita
V
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Fox
Jonathan H
JH
Lieberman
Greg
G
Dorsey
Kathryn
K
Matson
Wayne
W
Waldmeier
Peter
P
Housman
David E
DE
Kazantsev
Aleksey
A
Young
Anne B
AB
Hersch
Steven
S
D000813:Anilides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001284:Atrophy / Q000188:drug therapy; D001812:Blood-Brain Barrier / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000813:Anilides; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; C524875:N-(4-bromophenyl) 3-(4-bromophenylaminosulfonyl)benzamide; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D013449:Sulfonamides