Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot–Marie–Tooth Disease

Abstract

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500. The degeneration of motor and sensory nerve axons leads to motor and sensory symptoms that progress over time and have an important impact on the daily life of these patients. Currently, there is no curative treatment available. Recently, we identified histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, as a potential therapeutic target in axonal CMT (CMT2). Pharmacological inhibition of the deacetylating function of HDAC6 reversed the motor and sensory deficits in a mouse model for mutant “small heat shock protein B1” (HSPB1)-induced CMT2 at the behavioral and electrophysiological level. In order to translate this potential therapeutic strategy into a clinical application, small drug-like molecules that are potent and selective HDAC6 inhibitors are essential. To screen for these, we developed a method that consisted of 3 distinct phases and that was based on the pathological findings in the mutant HSPB1-induced CMT2 mouse model. Three different inhibitors (ACY-738, ACY-775, and ACY-1215) were tested and demonstrated to be both potent and selective HDAC6 inhibitors. Moreover, these inhibitors increased the innervation of the neuromuscular junctions in the gastrocnemius muscle and improved the motor and sensory nerve conduction, confirming that HDAC6 inhibition is a potential therapeutic strategy in CMT2. Furthermore, ACY-1215 is an interesting lead molecule as it is currently tested in clinical trials for cancer. Taken together, these results may speed up the translation of pharmacological inhibition of HDAC6 into a therapy against CMT2.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0501-z) contains supplementary material, which is available to authorized users.

Complex neuroprotective and neurotoxic effects of histone deacetylases

“…While most previous studies have utilized tubacin to inhibit HDAC6, other inhibitors have been recently developed with better pharmacological properties (Wang et al 2017). These HDAC6-selective inhibitors have been shown to ameliorate disease phenotypes in mouse models of Alzheimer's disease (Zhang et al 2014), Charcot-Marie-Tooth disease (Benoy et al 2017), and in cell culture models of Huntington's disease (Guedes-Dias et al 2015) and tauopathy (Cook et al 2014), confirming earlier findings. Based on their well demonstrated beneficial effects, HDAC6 inhibitors may represent a promising therapeutic approach against different neurodegenerative diseases.…”

“…), Charcot‐Marie‐Tooth disease (Benoy et al . ), and in cell culture models of Huntington's disease (Guedes‐Dias et al . ) and tauopathy (Cook et al .…”

Elongator subunit 3 (ELP3) modifies ALS through tRNA modification

“…Sensory nerve action potentials (SNAPs) were measured by supramaximal stimulation (6 pulse/s, 0.1 ms stimulus duration) at the distal tip of the tail and were measured 4 cm proximal in the tail. For SNAP recordings, multiple traces were averaged ( 43 ).…”

A novel histone deacetylase 6 inhibitor improves myelination of Schwann cells in a model of Charcot–Marie–Tooth disease type 1A

“…HDAC6 inhibition has been reported to enhance axonal transport and, thus, improve neuronal function (Adalbert et al, 2020;Benoy et al, 2017Benoy et al, , 2018d'Ydewalle et al, 2011;Mo et al, 2018). (Figure 2b,c).…”