SAINT LOUIS, MO, United States
SAINT LOUIS, MO, United States

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This invention provides new methods of treating subjects with fibroproliferative disease such as pulmonary hypertension (e.g. pulmonary arterial hypertensions), posthrombotic syndrome associated with venous thrombosis, or ventricular heart failure associated with fibroproliferative disease. In each case, the treatment methods of the present invention comprise administering apyrase agentsfor example, a soluble agent belonging to the class of CD39 apyrases, optionally CD39L apyrase family, or optionally CD39L3 apyrases. Also provided are methods of diagnosing pulmonary arterial hypertension comprising quantifying cytokines in biological fluids and examining the values for those elevated in comparison to normal control values.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 288.30K | Year: 2013

DESCRIPTION (provided by applicant): Bone metastasis is common in patients with advanced breast, prostate, and lung cancers as these tumors have a remarkable ability to metastasize to bone. Two-thirds of patients with metastatic bone cancer experience severe pain which is usually described as dull in character, constant in presentation, and gradually increasing in intensity with time. Bone cancer pain is one of the most difficult of all persistent pains to control because the metastases are generally not limited to a single site and bone cancer pain is associated with unique pathophysiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used an- algesics, but are limited by significant adverse side effects, such as gastric bleeding and neuropsychiatric symptoms. APT102 is a proprietary, optimized human apyrase of the CD39 family. APT102 selectively scav- enges excess pro-inflammatory and algogenic ATP and pro-metastatic ADP to AMP, thereby attenuating vas- cular inflammation,preventing metastasis, and reducing pain. Ubiquitous CD73 further metabolizes AMP to adenosine, which has been shown to reduce neuropathic pain in humans. Hence, the analgesic effect of APT102 results both from the elimination of ATP and from the production of adenosine. In the proposed studies, we will evaluate the dose-response of APT102 in a model of osteolytic bone cancer pain. This model is driven by in- tra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells and closely mirrors the human condition. We also will determine the potential side effects of APT102 in the rotarod and Functional Observa- tional Battery (FOB) assays in healthy rats. The long-term goal is to develop APT102 as a safe and effective analgesic therapy. Weekly orbi-weekly dosing will provide sustained pain relief for bone cancer pain patients without significant side effects or addiction. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The analgesic effect of human apyrase results both from the elimination of ATP and from the production of adenosine. In the proposed studies, we will evaluate the dose-response of APT102, an optimized human apyrase, in a model of osteolytic bone cancer pain. The long-term goal is to develop APT102 as a safe and effectiveanalgesic therapy for bone cancer pain patients without significant side effects or addiction.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

Systemic lupus erythematosus SLE is a prototypic autoimmune disease that affects at least million Americans Current immunosuppressive treatments are effective but can be accompanied by infections and toxicity especially when applied over a longer period of time Hence there remains a significant unmet need for safe and more effective treatments It is well established that patients with SLE are marked by reduced regulatory T cells and acquired deficiency of interleukin IL Transient treatment with low dose recombinant IL increases regulatory T cell number while blocking T follicular helper cells Hence the treatment reduced autoantibody formation and immune complex deposition without inducing systemic immune suppression These data strongly support development of IL based therapy Importantly low dose rIL therapy safely achieved significant efficacy in a small clinical trial However current low dose rIL therapy has a very short half life and causes local reaction at injection sites with an unwanted increase in several innate immune cell types such as natural killer cells and eosinophils To obtain ideal outcomes in patients we have designed a long acting IL analog APT that promises to generate low and stable circulating levels of IL related agonist The innovative drug candidate will enable selective stimulation of regulatory T cells while minimizing negative clinical effects Importantly a better efficacy and safety profile has been demonstrated in multiple animal models The specific aim of this Phase I SBIR proposal is to determine whether twice weekly treatment with mAPT for weeks will more effectively halt the disease progression for days of follow up compared with low dose rmIL recombinant murine IL in the mouse model of SLE at the time of disease onset The innovative approach involves the treatment with a novel IL analog APT to restore regulatory T cell function in systemic lupus erythematosus SLE that will arrest the autoimmune process and thereby halt disease progression


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 298.49K | Year: 2015

DESCRIPTION provided by applicant Type diabetes is an immune mediated disease in which insulin producing beta cells are destroyed resulting in life long dependence on exogenous insulin The number of patients being diagnosed is increasing each year particularly in the very young Despite advances in glucose monitoring and insulin delivery there is a compelling need to identify therapies that may safely alter the course of immune mediated beta cell destruction and preserve and even increase beta cell function It is well established that patients with type diabetes are marked by defects in regulatory T cells and or interleukin IL or its receptor signaling that controls autoimmunity Transient treatment with low dose recombinant IL increased regulatory T cell number and induced the persistence of repaired IL responsiveness in diabetic patients These clinical data strongly support further development of IL based therapy However current low dose rIL therapy has a very short half life with an unwanted increase in several innate immune cells types such as natural killer cells and eosinophils To obtain ideal outcomes in patients who are mostly young and feel otherwise healthy and have little short term morbidity we have designed a long acting IL analog that promises to generate low and stable circulating levels of IL related agonist The IL analog effectively binds to high affinity trimolecular IL R complex but not the intermediate affinity bimolecular IL R complex e g natural killer cells eosinophils Only regulatory T cells and newly activated previously na ve T cells express the high affinity IL R While IL is essential for the viability and functional integrity of regulatory T cells IL is actually a death factor fr newly activated T effector cells Hence the innovative drug candidate at low dose will enable selective stimulation of regulatory T cells and transient or intermittent administration while minimizing negative clinical effects Importantly a better efficacy and safety profile has been demonstrated in multiple animal models The specific aim of this Phase I SBIR proposal is to determine whether twice weekly treatment with the innovative IL analog for weeks will more effectively restore euglycemia for weeks of follow up than daily treatment of rIL for weeks in spontaneous new onset onset of andlt hours diabetic NOD mice PUBLIC HEALTH RELEVANCE The innovative approach involves the treatment with a novel IL analog to restore regulatory T cell function in Type diabetes mellitus that will arrest the autoimmune process and thereby preserve residual insulin production


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 297.41K | Year: 2015

DESCRIPTION provided by applicant Despite evidence that inflammatory mechanisms initiate and complicate pathophysiology in pulmonary arterial hypertension PAH no strategies have been developed to target the inflammatory cells involved Moreover it has been known for years that autoimmune diseases are associated with certain forms of PAH Hence novel therapy is urgently needed to attenuate chronic inflammation restore immune homeostasis and reverse adverse vascular remodeling in order to achieve a persistent improvement of pulmonary and right ventricular functions Naturally occurring thymus derived CD CD Foxp regulatory T cells nTreg play vital roles in controlling excessive inflammatory responses and prevent autoimmune disease Interleukin IL is the key cytokine for the generation survival and function of nTreg by direct binding to its high affinity receptor consisting of three subunits IL R CD IL R CD and c CD Recent clinical trial shows that treatment with low dose IL increased nTreg cells population and was associated with reversal of glucocorticoid refractory chronic graft versus host disease in patients who had undergone allogeneic hematopoietic stem cell transplantation We have designed APT a fusion protein of human serum albumin HSA and IL produced in mammalian cells The unglycosylated fusion protein kD improves solubility and the in vitro potency by fold and extends plasma half life by fold h A single mutation was introduced to eliminate the interaction with endothelial cell and lower the risk of vascular leak syndrome Hence low dose APT will enable safe selective and convenient stimulation of nTreg cells with high affinity to IL R receptors while minimizing activation of effector immune cells with intermediate affinity IL R receptors In the severe and andquot irreversibleandquot PAH model induced by SU hypoxia in rats which resembles human PAH pathophysiology characterized by systemic inflammation and oxidative stress treatment with APT twice a week for weeks effectively restored immune homeostasis and attenuated fibrosis which lead to reversal of lung and RV function In contrast neither bosentan FDA approved first line vasodilative therapy nor Gleevec effective but toxic in Phase III trial were safe or effective In this Phase I SBIR grant application we will determie whether transient treatment with APT will achieve long term improvement of pulmonary and RV function Specific Aim Determine whether treatment of APT twice a week for weeks initiated days after PAH induction will safely reverse pulmonary and RV remodeling and function weeks of follow up post the treatment in the rat model of SU hypoxia induced severe PAH PUBLIC HEALTH RELEVANCE We will determine whether transient or intermittent treatment with a novel and proprietary immunomodulatory drug will improve lung and heart functions in the clinically relevant animal models of human pulmonary arterial hypertension


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 299.79K | Year: 2015

DESCRIPTION provided by applicant Neuropathic pain such as diabetic neuropathic pain DNP can be difficult to treat with only of patients achieving meaningful andgt pain relief Current therapies e g duloxeline mainly address symptoms by focusing on blocking neurotransmission in the pain pathway with limited efficacy potentially severe side effects and narrow therapeutic index Hence novel therapies are needed to safely manage symptoms and also target the underlying pathophysiological mechanisms that will improve the functional status and life quality of affected patients APT an optimized human apyrase selectively scavenges excess pro inflammatory and algogenic extracellular ATP eATP and ADP eADP and metabolizes them to eAMP thereby attenuating vascular or central inflammation and pain Ubiquitous CD further metabolizes eAMP to adenosine which has been shown to reduce neuropathic pain in animals and humans It has been shown that administration of APT exhibited a long lasting days anti hyperalgesic effect in the model of Complete Freudandapos s Adjuvant induced inflammatory pain with no noticeable side effects In the proposed studies we will evaluate the dose response of APT in both the chronic constriction injury CCI model of neuropathy and the model of STZ induced diabetic neuropathy We also will determine the potential side effects of APT using the rotarod and functional observational battery assays in healthy rats Specific Aim To determine whether APT s c will abrogate neuropathic pain in the CCI model in rats without behavioral side effects Specific Aim To determine whether APT s c will abrogate neuropathic pain in the STZ induced diabetic model in rats without significant side effects The long term goal is to develop APT as a safe and disease modifying analgesic therapy Weekly or monthly dosing will provide sustained pain relief for neuropathic pain patients without significant side effects tolerance or addiction PUBLIC HEALTH RELEVANCE We will determine whether an optimized human apyrase will abrogate diabetic neuropathic pain without behavioral side effects in animal models


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.88K | Year: 2014

DESCRIPTION (provided by applicant): It has been recently shown that CD4+ and CD8+ T lymphocytes are critically involved in the collateral brain injury and neurological deficit associated with experimental stroke. Naturally occurring CD4+CD25+Foxp3+ (nTreg) cells derived from thymus play a key role in modulating the function of effector T cells and antigen- presenting cells that maintain self tolerance and immunological homeostasis. In the experimental models of stroke, deletion of nTreg cells profoundly increased delayed brain damage and deteriorated functional outcome in mice. Conversely, administration of nTreg cells resulted in a marked reduction of brain infarct and improvement of neurological functions while attenuating blood-brain barrier disruption with therapeutic window of at least 24 h. Remarkably, nTreg cell treatment corrected poststroke lymphopenia and decreased bacterial loads in the blood during recovery. Hence, nTreg cells represent a potentially safe and powerful approach for stroke the


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.14K | Year: 2014

DESCRIPTION (provided by applicant): Cardiopoietic cell therapy significantly improved left ventricular function, blunted pathological remodeling, and functional outcomes in animal models and Phase I/II clinical trial of heart failure patients. There is ongoing Phase III trial. In this therapeutic approach, bone marrow-derived mesenchymal stem cells are engaged into cardiac stem cells by exposing to a cardiogenic cocktail of growth factors, including activin A, transforming growth factor-b1, and bone morphogenetic protein-4, which is the single largest cost component of clinical manufacturing. These cytokines all belong to the TGF-b superfamily, which are critical for cardiopoietic stem cell expansion and differentiation. However, due to the complex post-proteolytic modifications and poor solubility at neutral pH, yield from all the curren manufacturing process is very low, and as a result bulk volume is uneconomical and not readily available. Currently, commercial products are transiently produced in no


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 968.16K | Year: 2016

Principal Investigator Program Director Last First Middle Chen Ridong Abstract There remains a crucial unmet medical need in acute ischemic stroke AIS treatment Approximately of patients die within one year and are permanently disabled making AIS the fourth leading cause of death and the leading cause of adult disability in the USA with an estimated cost range of $ billion annually Recombinant tissue plasminogen activator rt PA is the only drug approved by the FDA for restoring cerebral blood flow and improving patientandapos s functional outcome with no survival improvement Currently only of AIS patients receive rt PA as its use is limited by narrow time window of administration up to hours post symptom and fold increased intracranial hemorrhage Recently endovascular treatment with retrievable stents has been shown to improve the outcomes in small subpopulation of patients with proximal vessel occlusion The failures of numerous neuroprotective therapies in clinical trials suggest that neuroprotection alone without restoration of tissue perfusion may not be adequate for treatment of stroke Thus developing the combinational therapy of rt PA and or retrievable stents with human apyrase as a safe adjunctive antithrombotic that also will attenuate reperfusion and rt PA related hemorrhagic transformation will be of great importance for stroke patients that promises to extend the time window and improve clinical outcome and survival APT is a proprietary and optimized human apyrase which is a homolog of CD Administration of multi functional APT scavenges pro thrombotic ADP and pro inflammatory ATP which are both released at sites of thrombosis and injury Hence co administration of APT with rt PA will prevent thrombotic re occlusion and maintain vascular integrity necessary to prevent hemorrhagic transformation The efficacy and safety of APT in combination with rt PA has been demonstrated in the clinically relevant models of thrombo embolic stroke adult and aged animals in two independent laboratories as recommended by the Stroke Therapy Academic Industry Roundtable funded by a Phase II SBIR grant R NS Therefore this CRP project is well positioned to successfully advance APT to IND Specifically we propose Develop APT production process and validate IND enabling study plan with FDA Establish protocols for manufacturing cGMP Current Good Manufacturing Practice drug product for toxicology and IND filing Evaluate APT for safety in nonclinical toxicology studies and Prepare and file IND application With the successful filing of IND we will perform Phase I clinical trials of APT to obtain safety pharmacokinetic and pharmacodynamic biomarker data in healthy volunteers and then Phase II and III trials for stroke patients The long term goal of this project is to market APT as combination treatment with r tPA to provide a highly effective and safe acute therapy for AIS with at least a h treatment window This treatment regimen could be used by emergency room physicians and even in a mobile stroke unit to achieve faster prehospital treatment with rt PA for over of AIS patients to improve functional outcomes as well as survival a dramatic increase from the of AIS patients currently treated with r tPA which does not provide survival benefit Principal Investigator Program Director Last First Middle Chen Ridong Narrative The efficacy and safety of combining an optimized human apyrase with r tPA has been demonstrated unequivocally in several relevant models of thrombo embolic stroke including in the stroke model of aged rats With a strong interdisciplinary drug development team we propose to complete activities necessary to enable IND filing


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 299.20K | Year: 2016

DESCRIPTION provided by applicant Principal Investigator Program Director Last First Middle Chen Ridong Abstract Type diabetes T D is a leading cause of cardiovascular disease renal failure blindness amputations and hospitalization Up to of T D patients are overweight or obese which induces chronic low grade inflammation of adipose tissue and promotes insulin resistance and T D Moreover weight gain is the common side effect of older anti diabetic drugs Current therapies are not a cure and require daily administration Hence novel therapy that improves glucose control while simultaneously reducing body weight is urgently needed CD CD Foxp regulatory T cells Treg modulate inflammation and insulin resistance Very interestingly Treg cells with a unique phenotype are highly enriched in the visceral adipose tissue VAT of normal animals but their numbers are strikingly and specifically reduced in insulin resistant models of obese animals Importantly decreased numbers of Treg are also found in obese human omental Interleukin IL is the key cytokine for the generation survival and function of Treg by direct binding to its high affinity receptor Hence restoration of VAT Treg cells with low dose IL may offer a novel strategy for mitigating obesity related low grade inflammation and reversing insulin resistance and T D We have designed an IL based therapy that will enable selective stimulation of Tregs In the proposed Phase I SBIR study we will determine whether weekly treatment for weeks leads to improvement of insulin sensitivity and glucose control while reducing excessive body weight gain in the T D models of obese db db mice and diet induced obese mice The long term goal of this project is to develop a novel treatment weekly or bi weekly for T D alone or in combination with current therapies to improve glucose homeostasis and attenuate diabetes associated complications while simultaneously reducing excessive body weight gain PUBLIC HEALTH RELEVANCE The proposed approach involves the treatment of Type Diabetes Mellitus with weekly dosing of a novel immunomodulator in order to attenuate obesity induced low grade inflammation improve glucose control and reduce excessive body weight gain

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