Drug addiction is a serious, and growing, public health problem in the US. Combining medications with cognitive behavioral therapy (CBT) is an effective way for patients to attain and sustain abstinence, yet current safe medications are limited and there are no FDA-approved therapeutics for cocaine addiction, where CBT alone has poor success and relapse rates are high. Histone deacetylase (HDAC) inhibitors such as SAHA (Vorinostat) or sodium butyrate facilitate extinction of drug-seeking in animal models, consistent with the growing understanding of epigenetic mechanisms in learning and memory, and providing proof of concept for such a pharmacotherapeutic approach. 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 genetic or pharmacological inhibition of HDAC3 persistently enhances long-term memory. Furthermore, blocking HDAC3 pharmacologically or genetically enhances extinction of drug-seeking behavior and blocks reinstatement. Preliminary Data: KDAc Therapeutics is developing novel, highly optimized selective HDAC3 inhibitors and our lead development candidate, KDAC0001, has been extensively characterized in vitro and in vivo. Its preliminary pre-clinical ADME/PK/ toxicological profile, coupled with good CNS drug properties and initial efficacy in learning and memory paradigms, enables its use in definitive proof-of-concept studies in animal models of drug addiction. Hypothesis: We hypothesize that KDAC0001 or other KDAc compounds, when delivered at relatively safe exposure levels, will enhance extinction of drug-seeking behavior in rodent models, revealed as effects on rate of extinction across days and persistence of extinction against reinstatement challenges. Specific Aims: (1) Evaluate KDAC0001 in vivo efficacy and target engagement in two rodent models of addiction; (2) Develop and characterize second generation (2nd gen) novel compounds, focusing on improved HDAC selectivity, potency and CNS drug-like properties; and (3) Evaluate optimal 2nd gen compounds for in vivo efficacy and measure select surrogate markers to correlate behavioral effects with HDAC3 target engagement. This Phase I study will allow us to determine the feasibility of HDAC3 selective inhibition and demonstrate definitive proof of concept in models of drug addiction. Specifically, we aim to establish robust efficacy with an HDAC3-selective KDAc compound, and will define both the necessary compound attributes needed for efficacy and the therapeutic window, and identify a suitable development candidate as co-therapy to prevent relapse of drug addiction.
Public Health Relevance Statement: Public Health Relevance: Extensive brain research has deepened our understanding of the circuitry underlying many complex behaviors, revealing that drug addiction can also be viewed as a disease of learning and memory, with classic Pavlovian conditioning at play--essentially reinforcing the behaviors of drug addiction, and helping explain the neurobiological challenges of attaining and sustaining drug abstinence when reliant solely on cognitive behavioral therapy (CBT). One key process of memory formation that neurobehavioral research has identified and implicated in drug addiction is that of extinction. KDAc Therapeutics has developed compounds that enhance memory extinction and could potentially help prevent relapse in drug addiction; thus we seek to investigate these compounds in animal models of drug-seeking behavior.
NIH Spending Category: Anxiety Disorders; Behavioral and Social Science; Biotechnology; Brain Disorders; Drug Abuse (NIDA only); Genetics; Mental Health; Neurosciences; Post-Traumatic Stress Disorder (PTSD); Substance Abuse
Project Terms: Abstinence; Acetylation; addiction; Address; Animal Model; Atlases; Back; base; Behavior; Behavioral; Benchmarking; Biological; Brain; brain research; classical conditioning; Cocaine; Cocaine Dependence; cocaine use; Cognitive Therapy; Combined Modality Therapy; Comorbidity; Complex; Coupled; Data; design; Development; Disease; disorder later incidence prevention; Dose; Dose-Limiting; drug abstinence; Drug abuse; Drug Addiction; drug seeking behavior; Epigenetic Process; expectation; Extinction (Psychology); FDA approved; Fright; Funding; Gene Expression; Gene Targeting; Generations; Genetic; Gold; HDAC1 gene; HDAC11 gene; HDAC3 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; improved; In Vitro; in vivo; Individual; inhibitor/antagonist; Laboratories; Lead; lead series; Learning; learning extinction; Legal patent; Licensing; long term memory; Lysine; Measures; Memory; memory process; Methods; minimal risk; Modeling; Mus; neurobehavioral; Neurobiology; novel; novel therapeutics; Outcome; Patients; Persons; Pharmaceutical Preparations; Phase; phase 1 study; Play; Population; Positioning Attribute; Post-Traumatic Stress Disorders; pre-clinical; preference; prevent; Property; Protein Isoforms; Public Health; public health relevance; Rattus; reinforced behavior; Relapse; Reproducibility; Research; research clinical testing; response; Risk; Rodent Model; Seeds; Self Administration; small molecule therapeutics; Sodium Butyrate; Substance abuse problem; Substance Use Disorder; success; Surrogate Markers; Testing; Therapeutic; Therapeutic Index; Time; tool; Toxic effect; Translating; Treatment Efficacy; Triage; Vorinostat
