HDAC6 Inhibition and Ricolinostat Clause Samples

HDAC6 Inhibition and Ricolinostat. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from lysine residues on substrate proteins. The function of most HDACs is associated with gene transcription through modification of histone tail acetylation and regulation of chromatin dynamics. However, it has become apparent that some HDACs play a critical role in the regulation and function of lysine acetylation of non-histone proteins in most, if not all, major cellular functions (▇▇▇▇▇▇▇▇▇, 2009). In particular, HDAC6 is localized predominantly in the cytoplasm of cells where it is crucial in regulating the stability and function of microtubules (▇▇▇▇▇▇▇▇▇, 2002; ▇▇▇▇▇, 2003; ▇▇▇▇▇▇▇▇▇, 2009; ▇▇▇▇▇, 2010; ▇▇▇▇▇▇▇, 2013). Microtubule transport is a crucial component of neuronal survival (Sudo, 2010; ▇▇▇▇▇, 2010; ▇▇▇▇▇▇▇, 2009). HDAC6 activity has been associated with a loss in fast axonal transport, which requires stable microtubules (d’Ydewalle, 2011; ▇▇, 2014; ▇▇▇▇▇, 2013; ▇▇▇▇▇▇▇▇▇▇▇▇, 2013; ▇▇▇▇▇▇▇▇▇, 2007), and inhibition of HDAC6 with the selective inhibitor Tubastatin A reverses motor neuropathy in a mouse model of type 2 Charcot-▇▇▇▇▇-Tooth disease (d’Ydewalle, 2011). These data suggest that inhibition of HDAC6 in peripheral neurons may preserve neuron function and reverse or ameliorate the axonal degeneration observed in peripheral neuropathies such as those common in patients with diabetes.‌‌ Ricolinostat is a potent inhibitor of HDAC6 activity (enzymatic IC50 value of 4.7 nM), is 10- to 12-fold less active against Class I HDAC enzymes (HDAC1, 2, 3, and 8), and has minimal activity against Class IIa HDAC enzymes (HDAC4, 5, 7, and 9). HDAC6 is the primary deacetylase enzyme for alpha tubulin (▇▇▇▇▇▇▇▇▇, 2002). Ricolinostat treatment increased the level of acetylated α-tubulin in primary rat dorsal root ganglion neurons. In a human neuroblastoma cell line, ricolinostat increased the level of acetylated α-tubulin in a dose-dependent manner. Neurons are particularly sensitive to disruptions in intracellular transport via the microtubule network. Transport of mitochondria from the cell body to the nerve terminal through the axon (anteriograde transport), as well as transport back to the cell body (retrograde transport), are disrupted in many neurological conditions. Treatment of cultured dorsal root ganglion neurons with high glucose decreases transport in both directions. Pre-Treatment of the cells with ricolinostat prevents the disruption in mitochondrial transport. Di...
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  • PSN or Public Services Network The Public Services Network (PSN) is the government’s high performance network which helps public sector organisations work together, reduce duplication and share resources. Regulatory body or bodies Government departments and other bodies which, whether under statute, codes of practice or otherwise, are entitled to investigate or influence the matters dealt with in this Call-Off Contract. Relevant person Any employee, agent, servant, or representative of the Buyer, any other public body or person employed by or on behalf of the Buyer, or any other public body. Relevant Transfer A transfer of employment to which the employment regulations applies. Replacement Services Any services which are the same as or substantially similar to any of the Services and which the Buyer receives in substitution for any of the services after the expiry or Ending or partial Ending of the Call- Off Contract, whether those services are provided by the Buyer or a third party. Replacement supplier Any third-party service provider of replacement services appointed by the Buyer (or where the Buyer is providing replacement Services for its own account, the Buyer). Security management plan The Supplier's security management plan developed by the Supplier in accordance with clause 16.