HDAC6, a cytoplasmic 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.
The approach of Augustine Therapeutics can provide unique therapeutic solutions for patients suffering from neurological disorders with axonal dysfunction.
Our drug discovery efforts are mainly focused on finding appropriate drug candidates for Charcot–Marie–Tooth disease (CMT). Although considered a rare disease, CMT is the most common hereditary disorder of the peripheral nervous system, affecting approximately 3 million people worldwide. It is passed down through families, often in an autosomal dominant fashion. The disease becomes evident in early adulthood and then slowly progresses. Patients face progressive muscle weakness and loss of sensation in extremities, often accompanied by severe pain and cramps. CMT has a devastating impact on patients' quality of life, not only physically but also emotionally. Currently, no curative treatment is available. There are over 1000 mutations in more than 100 different genes known to cause CMT. They either directly disrupt myelin (CMT type 1) or axon integrity (CMT type 2) of peripheral nerves that control movement and sensation, affecting their function. Clinically, the different types are indistinguishable. The heterogeneity underlying CMT adds to the complexity of drug development for this devastating disorder.
At Augustine Therapeutics, we are developing novel medicines that target the underlying disease processes of CMT. Despite the genetic complexity in CMT, axon degeneration of peripheral nerves is at the root of all CMT type 2 subtypes, but it is also a secondary phenomenon in all other types of CMT. In CMT1 and CMT2 mouse models with different underlying genetic mutations, selective HDAC6 inhibitors have been shown to lead to reinnervation and effectively reverse disease symptoms. Our lead candidate can deliver the first truly curative option for CMT patients.
Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling adverse effect that is correlated with a few widely used chemotherapeutic drugs. It is caused by damage of the anti-cancer drugs to the peripheral nerves that control the sensations of our arms, legs, hands, and feet. Approximately sixty percent of chemo-patients suffer from symptoms such as decreased sensation and tingling of the extremities, often accompanied by severe pain and difficulties to walk and balance. CIPN can make activities of daily living, such as cooking, dressing, sleeping, and social interactions difficult. The symptoms can appear during the cancer treatment, but frequently persist or even worsen long after the chemotherapy has ended. Unlike most other types of pain, neuropathic pain does not improve with common painkillers, leaving this clinical challenge unresolved.
In preclinical studies, HDAC6 inhibitors have been shown to produce not only a robust curative effect but also a preventive effect, without impairing the anticancer activity of the chemotherapy. A great advantage to the latter approach is that our drugs can be administered as a co-treatment with chemo-agents since the nerve damage occurs only when the anticancer treatment has been initiated. This will likely improve the chance of success. Interestingly, HDAC6 is also accepted as an anticancer target, and specific inhibitors are currently being tested for treating different types of cancer.
In addition to peripheral neuropathies like CMT, our HDAC6 asset has potential applications in neurodegenerative disorders of the central nervous system, such as amyotrophic lateral sclerosis (ALS). ALS is an incurable disease in which the motor neurons controlling the muscles gradually die off, resulting in muscle weakness, muscle wasting, and eventually paralysis and death.
In approximately 10% of cases, ALS runs in families, but most of the time, ALS is not inherited. Over 20 genes are currently linked to the disease. Several of these genes are implicated in axonal transport. Moreover, cellular inclusions containing the protein TDP‑43, which are found in most ALS patients, are associated with defects in axonal transport.
Similar to what is observed in peripheral neuropathies, HDAC6 inhibitors are very effective in restoring axonal transport in diseased neurons of the central nervous system. Moreover, experiments in mutant TDP-43 motor neurons have demonstrated that HDAC6 inhibitors can counteract the early stages of TDP-43 pathologies, such as TDP-43 mislocalization and the accumulation of insoluble TDP-43. Based on these insights, we are developing a new generation of safe HDAC6 inhibitors that is suitable for long-term use and is able to cross the brain-blood barrier.
