Michael Brownstein - US grants

DESCRIPTION (provided by applicant): Vasopressin (AVP) antagonists represent a novel therapeutic class for the treatment of depression. The potential utility of these compounds has emerged from observations in depressed individuals, findings in animal models, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. This Fast Track proposal seeks support for the identification of novel mixed vasopressin 1a/1b (V1a/V1b) receptor antagonists and the preclinical development of recently discovered molecules in this class that already demonstrate excellent biological activity in vitro. The scientific basis for mixed V1a/V1b antagonists as a pharmacotherapy for depression includes: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of depression, 2) recognition that AVP, not CRF, drives HPA function associated with chronic psychological stress, and 3) the localization of V1a and V1b receptors in regions involved in the control of social behaviors and HPA axis regulation (V1a in limbic system;V1b in limbic system and anterior pituitary). The initial development of these mixed antagonists to date has been supported by private sector venture funding. SBIR Fast Track support will enable essential preclinical development work that will advance candidate molecules to the stage where bulk synthesis and IND-enabling toxicology can be undertaken. Bringing candidates to this status will accelerate commercialization opportunities by significantly enhancing the likelihood of additional private financial investment or a co-development partnership structure with a major pharmaceutical house. PUBLIC HEALTH RELEVANCE: The public health need for new pharmaceutical treatments for depression is well documented. Depression affects some 20 million Americans each year and carries a conservatively estimated annual total economic burden of $125 billion. Existing drugs for depression are not uniformly effective, frequently have undesirable side effects, and do not help some 50% of individuals suffering from the disorder according to recent estimates. These limitations demonstrate that a new treatment approach through mixed V1a/V1b receptor antagonism may offer a significant opportunity for improved outcomes with substantial societal benefit.

New paradigms for socio-technical knowledge exchange, especially within and across academic disciplines, is important in order to generate insights about how new knowledge is (and can be) created. Academic researchers regularly use Web-based tools such as wikis, blogs, electronic repositories and open publishing systems to promote the open exchange of knowledge, but with varied levels of success. This work creates an open knowledge exchange system that is based on socio-technical principles, one conducive to collaborative research and the generation of new knowledge. This work will facilitate an egalitarian review process, provide support for micro-contributions as well as full-length reviews of working papers, and allow for immediate feedback on the relevance and utility of contributions. The work begins with a conceptual design and develops a socio-technical system comprised of existing tools as the basis for a KES openly accessible and available to all. It will gather data for future analysis of user behaviors and outcomes to assess the relevance, adequacy and performance of the system?s functional elements.

Intellectual Merit: This work will identify new knowledge about the participants, interactions, and contributions required for a successful, community-mediated system of open academic exchange.

Broader Impact: OKES will provide a research-driven blueprint for launching and operating an open, academic knowledge exchange, which promises to enrich the academic research climate for many fields. It will help students and practitioners in industry more actively engage in knowledge generation, and produce a rich research dataset to support follow-on studies.

? DESCRIPTION (provided by applicant): Huntington's Disease (HD) is an inherited disease that results from expansion of a trinucleotide (CAG, cytosine/adenine/guanine) repeat that encodes a polyglutamine tract in the huntingtin protein. Psychiatric symptoms, including irritability and aggression, are common in HD patients. These are among the most distressing aspects of the disease. They have adverse effects on daily life and often result in institutionalization. Despite the frequent occurrence and severe consequences of irritability and aggression in HD, these symptoms have received little attention to date. Effective treatments are lacking and well-validated scales for measuring changes in these symptoms are not available. Faced with a significant unmet need, neurologists cannot currently determine whether new drug therapies might be useful in treating neuropsychiatric symptoms in HD. The Phase II clinical trial we propose in HD patients (n=108), A randomized, placebo controlled, double blind, multi-center study to assess the tolerability of SRX246 in irritable/aggressive subjects wit Huntington's Disease (HD), will allow us to rigorously evaluate the tolerability of a potential ne drug for the treatment of irritability and aggression. It will also provide additional safety data n the compound and explore various rating scales for the assessment of changes in these symptoms. Thus, we will obtain critical data that can be used to plan future Phase II or III clinicl trials of drugs that might blunt irritability and aggression in HD. The compound that we propose to test is SRX246, a first-in-class vasopressin 1a (V1a) receptor antagonist. SRX246 crosses the blood-brain barrier following oral administration, exhibits high affinity and selectivity for is target receptor, has a strong safety profile, is well-tolerated in healthy volunteers, and has excellent pharmacokinetics. Extensive preclinical pharmacology studies and an experimental medicine fMRI study in healthy volunteers have shown that SRX246 has CNS effects after oral administration and that it modulates brain circuits involved in responses to stimuli that elicit aggression/fear. These findings strongly suggest that SRX246 might have a beneficial effect on the irritability and aggression seen in a sizable proportion of HD patients. The proposed project will generate data needed to plan a future clinical trial that can rigorously test SRX246 for efficacy as a treatment for irritability and aggression.

Project Summary/Abstract Traumatic Brain Injury (TBI) contributes to a third of injury-related deaths in the US and is among the leading causes of death and disability in people under 35 and over 65. Recent statistics show that TBI annually causes 50,000 deaths, 275,000 hospital admissions, carries an average lifetime expense of $550,000/patient, and an annual economic burden conservatively estimated at $86 billion. The lack of any approved drugs that prevent, minimize, or reverse the brain damage and deficits caused by moderate to severe TBI is a critical unmet need. We propose to test a novel class of vasopressin 1a (V1a) receptor antagonists as a new treatment to meet this need. There is a strong scientific rationale for V1a receptor antagonism as a disease-modifying pharmacotherapy for moderate to severe TBI. Brain edema following TBI is associated with poor prognosis. Following TBI, increased vasopressin (AVP) expression, acting through the V1a receptor, is a major driver of cerebral edema. We recently found that 5 days of treatment with one of Azevan's novel, blood-brain barrier (BBB) penetrating V1a antagonists beginning 24 hr after moderate TBI was induced using the momentum exchange model significantly reduced cerebral edema and eliminated cognitive deficits in concussed animals. The proposed studies will confirm and build on these encouraging preliminary findings. Using the momentum exchange model to induce moderate TBI in female and male rats with a single head strike, four candidate compounds will be screened in physiological, imaging, behavioral, and pharmacokinetic experiments. The compounds will be tested to characterize their effects on 1) edema and resting state functional connectivity using MRI; 2) plasma biomarkers (S100b, GFAP, UCH-l1) in the first 24 hours post-injury that are known to reflect injury severity in rats and humans; and 3) cognitive function based on performance on the Novel Object Recognition task and Barnes Maze test. Finally, we will measure plasma levels of the 4 candidate compounds after intravenous, intraperitoneal, and oral gavage administration. Serial sampling of blood will allow calculation of pharmacokinetic (PK) parameters. These data will help inform planning for studies to help optimize route of administration and formulations for use in treating moderate to severe TBI. The two compounds that most effectively reduce edema, improve rsFC, eliminate cognitive deficits on both tests, and exhibit the best PK profiles (e.g., IV and oral availability, t1/2, AUC) will be designated for continued development in Phase 2, where further IND-enabling work (mechanistic studies, formulation, safety & toxicology) will be undertaken.