KDAc Therapeutics, Inc. — Department of Health and Human Services SBIR Phase I: 101

Description

DESCRIPTION provided by applicant Post traumatic stress disorder PTSD is a major health problem affecting over 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 HDAC isoforms b not safe for non oncological application toxicity driven by both HDAC 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 HDAC is the best target as i genetic or pharmacological inhibition of HDAC persistently enhances long term memory ii an HDAC selective inhibitor CI increased synaptic plasticity attenuated remote fear memories and enhanced extinction in a classic mouse model of fear conditioning iii HDAC has the least homology to HDACs and offering unique and distinctive rational design approaches towards high isoform selectivity and iv KDAc Therapeuticsandapos HDAC selective inhibitors have demonstrated improved safety and tolerability mitigating known dose limiting toxicities driven by HDAC inhibition Our lead development candidate KDAC a novel highly optimized HDAC 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 HDAC 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 HDAC inhibition in enhancing fear extinction with highly HDAC selective inhibitors Our long term goal is to develop an HDAC 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 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 patientsandapos 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