?Post-traumatic stress disorder (PTSD) is a major health problem, affecting over 5 million Americans every year. Despite advances in behavioral treatment approaches (e.g., prolonged exposure therapy (PE, a form of cognitive behavioral therapy (CBT)) and the more recently adopted paradigm of combining PE/CBT with medications to augment fear extinction learning, these pharmacotherapeutic approaches have had mixed success, and there is an urgent need for a broader array of effective medications for chronic PTSD. With the emerging understanding of PTSD as a learning and memory disorder generally, and a fear reflex disorder specifically, the opportunity to develop novel pharmacotherapeutics targeting mechanisms of fear extinction to expand beyond the current drugs that act at the level of synaptic receptors, has exciting potential. An increasing body of work has shown that epigenetic effects driven by nonspecific HDAC inhibitors (such as SAHA (Vorinostat), valproic acid (VPA) or sodium butyrate (NaB)) can facilitate and enhance fear extinction in multiple rodent models. The problem is that all FDA-approved and current pre-clinical HDAC inhibitors are (a) not sufficiently isoform selective (inhibiting many of the 11 HDAC isoforms), (b) not safe for non-oncological application (toxicity driven by both HDAC1/2 inhibition and off-target effects) and (c) have poor CNS drug-like properties. Highly isoform-selective HDAC inhibitors are needed to mitigate these risks and increase the therapeutic window. We believe HDAC3 is the best target, as (i) genetic or pharmacological inhibition of HDAC3 persistently enhances long-term memory, (ii) an HDAC1/2/3-selective inhibitor (CI-994) increased synaptic plasticity, attenuated remote fear memories, and enhanced extinction in a classic mouse model of fear conditioning; (iii) HDAC3 has the least homology to HDACs1 and 2, offering unique and distinctive rational design approaches towards high isoform selectivity; and (iv) KDAc Therapeutics' HDAC3-selective inhibitors have demonstrated improved safety and tolerability, mitigating known dose-limiting toxicities driven by HDAC1/2 inhibition. Our lead development candidate, KDAC0001, a novel highly optimized HDAC3-selective inhibitor, has been extensively characterized in vitro and in vivo, with a preliminary pre-clinical ADME/PK/ toxicological profile, good CNS drug properties and initial efficacy in learning and memory paradigms. Thus, with selective inhibitors in hand, we can enable a focused evaluation of the hypothesis that HDAC3-selective inhibition will be safe and effective in enhancing extinction (rate and persistence) in fear conditioning models. These proposed Phase I SBIR studies will not only test these molecules for application, and potential clinical translation, to PTSD, but wil also provide the first assessment of this mechanism (HDAC3 inhibition) in enhancing fear extinction with highly HDAC3-selective inhibitors. Our long-term goal is to develop an HDAC3- selective inhibitor as a novel small molecule therapeutic that would augment PE or CBT to enhance extinction learning in PTSD and promote persistent fear inhibition.
Public Health Relevance Statement: Public Health Relevance: The emerging understanding from basic neurobiology research of post-traumatic stress disorder (PTSD) as a learning and memory disorder has led to the currently most effective treatment approach of combining behavioral therapy with medications that target the neuronal circuits underlying fear learning and memory, to improve patients' responses. However, the only medications approved and in development do not take advantage of recent discoveries on mechanisms specific to fear extinction, which have great potential for improved and more precise pharmacotherapies. KDAc Therapeutics has developed compounds that enhance the rate and persistence of fear extinction in animal models of memory and fear conditioning, thus we seek to investigate these novel compounds and this novel mechanism in animal models of fear conditioning to determine their potential for translation to standard clinical treatments for PTSD.
Project Terms: Acetylation; Adopted; Affect; American; Animal Model; Attenuated; Back; base; BDNF gene; Behavior; Behavior Therapy; Behavioral; Benchmarking; Biological; Biological Assay; Brain; Brain region; Chronic Post Traumatic Stress Disorder; Clinical; clinical application; Clinical Treatment; Cognitive Therapy; Comorbidity; conditioned fear; Coupled; Data; design; Development; Disease; disorder later incidence prevention; Dose; Dose-Limiting; Drug abuse; Drug Addiction; drug seeking behavior; effective therapy; Epigenetic Process; Evaluation; Extinction (Psychology); FDA approved; fear memory; Fright; Gene Expression; Gene Targeting; Generations; Genetic; Goals; Hand; HDAC1 gene; HDAC3 gene; Health; Hippocampus (Brain); Histones; improved; In Vitro; in vivo; Individual; inhibitor/antagonist; Lead; lead series; Learning; Learning Disorders; learning extinction; Location; long term memory; Long-Term Potentiation; Lysine; Measures; Memory; Memory Disorders; minimal risk; Modeling; mouse model; Mus; Neurobiology; neuronal circuitry; Neurons; novel; novel therapeutics; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pilot Projects; Post-Traumatic Stress Disorders; pre-clinical; productivity loss; Property; Protein Isoforms; public health relevance; Quality of life; Rattus; reflex disorder; Research; Resistance; response; Risk; Rodent Model; Role; Safety; Slice; Small Business Innovation Research Grant; small molecule; small molecule therapeutics; Societies; Sodium Butyrate; Stress; success; Surrogate Markers; Synaptic plasticity; Synaptic Receptors; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translating; Translations; Treatment Efficacy; trend; Valproic Acid; Vorinostat
