HDAC6, a class II histone deacetylase, is a well-known molecular target in various diseases, and in particular neurodegenerative disorders and neuropathies.
HDAC6 enzyme plays a leading role in axonal protection and regeneration by controlling the efficiency of internal axonal transport. Because of their enormous length in relation to the soma -spanning up to more than one meter- axons strongly rely on an efficient transport system for the supply of organelles and nutrients to specific compartments. This finally ensures that neurons can properly conduct signals. At the cellular level, this enzyme helps clear aggregated proteins and influences axonal outgrowth. By deacetylating a protein named a-tubulin and binding to motor proteins, it can also hamper the axonal transport of essential cargoes (such as mitochondria) throughout the cell. This leads to cellular stress and triggers the neurodegenerative cascade.
Selectively inhibiting HDAC6 offers a unique opportunity to repair cellular, neuronal, and axonal defects characteristic of many diseases.
Augustine Therapeutics has discovered and developed a novel class of small molecules inhibiting selectively and specifically the HDAC6 enzyme. This novel generation of HDAC6 inhibitors (HDAC6i) are chemically-distinct and superior to the first generation hydroxamate-based inhibitors developed so far, known to display poor selectivity and pharmacokinetic profile as well as toxicity, making them unsuitable for the long-term use required to treat neurodegenerative disorders.
Augustine uses this novel and proprietary disease-modifying treatment approach to develop highly efficacious and safe drugs for patients suffering from neuromuscular and neurodegenerative disorders. Our lead program is in preclinical development aiming at delivering peripherally restricted and centrally targeting molecules for the treatment of CMT and CIPN.
Ludo Van Den Bosch, PhD: Scientific founder and Chairman of the Advisory Board
"This new generation of selective, orally bioavailable, and safe HDAC6i represents a life-changing breakthrough for patients suffering from neuromuscular and neurodegenerative diseases. In both disease mouse models, we saw a robust reversal of the disease, providing a disease-modifying therapy and potential cure for such disabling disorders. These discoveries will have a tremendous impact on patients worldwide”
Look at this overview article: Rossaert E, Van Den Bosch L. HDAC6 inhibitors: Translating genetic and molecular insights into therapy for axonal CMT. Brain Res. 2020; 1733:146692.