Literature Support

Supporting literature

Compelling evidence for therapeutic benefit of HDAC6 inhibition

Published literature

Extensive data from multiple research groups support Eikonizo’s approach for using HDAC6 inhibitors as a disease-modifying therapeutic for neurodegeneration in ALS and AD

HDAC6 deacetylates tau and tubulin, engaging key mechanisms relevant in neurodegeneration

Multiple HDAC6 inhibitor (HDAC6i) tool compounds have desired mechanistic effects in disease models

  1. Tseng JH, Xie L, Song S, Xie Y, Allen L, Ajit D, et al. The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. Cell Rep. 2017; PMID:28854366.

  2. D’Ydewalle C, Krishnan J, Chiheb DM, Van Damme P, Irobi J, Kozikowski AP, et al. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med. 2011;17(8):968–74. PMID:21785432.

  3. Selenica ML, Benner L, Housley SB, Manchec B, Lee DC, Nash KR, et al. Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition. Alzheimer’s Res Ther. 2014; PMID:24576665.

  4. Fan SJ, Huang FI, Liou JP, Yang CR. The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer’s disease model article. Cell Death Dis. 2018;9(6). PMID:29844403.

  5. Zhang L, Liu C, Wu J, Tao J-J, Sui X-L, Yao Z-G, et al. Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014 Jul 25;41(4):1193–205. PMID:24844691.

HDAC6 deacetylates tau and tubulin, engaging key mechanisms relevant in neurodegeneration

Tau

  1. Carlomagno Y, Chung D eun C, Yue M, Castanedes-Casey M, Madden BJ, Dunmore J, et al. An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function. J Biol Chem. 2017;292(37):15277–86. PMID:28760828.

  2. Tseng JH, Xie L, Song S, Xie Y, Allen L, Ajit D, et al. The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. Cell Rep. 2017; PMID:28854366.

  3. Cook C, Carlomagno Y, Gendron TF, Dunmore J, Scheffel K, Stetler C, et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum Mol Genet. 2014;23(1):104–16. PMID:23962722.

Tubulin

  1. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455–8. PMID:12024216.
  2. Dompierre JP, Godin JD, Charrin BC, Cordelières FP, King SJ, Humbert S, et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci. 2007 Mar 28;27(13):3571–83. PMID:17392473.