RESEARCH TRIANGLE PARK, NC, United States
RESEARCH TRIANGLE PARK, NC, United States
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Patent
Duke University and Cognosci, Inc. | Date: 2012-07-13

Provided are methods of predicting or assessing the level of severity of cancer or cancer progression in a patient comprising measuring levels of SET expression in a biological sample from a patient and comparing levels of SET expression to a control sample or standard value. Methods for predicting or evaluating the efficacy of a SET therapeutic and kits comprising at least one reagent for measuring SET protein expression are also provided.


Patent
Cognosci, Inc. | Date: 2014-11-12

Novel ApoE peptide derivatives and ApoE-protein transduction domain conjugates are disclosed which are useful for treating disorders including CNS inflammation, traumatic brain injury, inflammatory bowel disease (also known as Crohns Disease or ulcerative colitis), cerebral ischemia, atherosclerosis, sepsis, multiple sclerosis and arthritic diseases, Alzheimers Disease and other brain disorders. The invention encompasses methods for protecting subjects having undergone irradiation or radiotherapy by administration of ApoW or at least one ApoE mimetic peptide.


Patent
Cognosci, Inc. | Date: 2015-10-06

The present invention provides novel pharmaceutical compositions comprising ApoE-derived peptide dimers. In particular, the ApoE peptide dimers of the invention comprise at least two ApoE mimetic domains and can comprise one or more protein transduction domains. Methods of treating various conditions, such as cancer, inflammatory conditions, and neurodegenerative diseases, by administering the pharmaceutical compositions of the invention are also disclosed.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 261.82K | Year: 2012

DESCRIPTION (provided by applicant): Our overall goal is to market a COG compound (aka. apoE-mimetic peptides) for the treatment of patients with asthma. Cognosci has discovered, patented and published a novel series of COG compounds which are functionalmimetics of apolipoprotein-E. These COG compounds have profound anti-inflammatory activities in a wide variety of cell-based and animal-based models of human disease conditions (Vitek et al. 2011, Christensen et al. 2011, Li et al. 2008, Lynch et al. 2003,and others). The COG compounds are also extremely well tolerated in mice, rats and dogs following repeated daily dosing for as many as 90 days that was tested. In a totally unanticipated publication, Levine and colleagues at National Institutes of Heart,Lung and Blood (NHLBI) independently found that apoE-130-149 significantly reduced the signs, symptoms and characteristics of asthma in a house dust mite-induced model of asthma in mice. ApoE-130-149 is known to us as COG130, a patented composition of matter owned by Cognosci. These events have now put us in a unique position to verify and extend Levine's pioneering work in this Phase I proposal so that we can: 1) show that COG130 can be efficiently nebulized into an aerosol, and that the inhaled aerosol is well tolerated in single and repeat dosing in mice and 2) that inhaled COG130 produces a dose-dependent reduction of asthmatic characteristics in a House Dust Mite-induced model of asthma in mice. The data generated from the successful completion of theexperimental work plan in this proposal will lay the foundation for the medical, commercial and regulatory requirements that Cognosci will need to fully develop to move a COG compound into clinical use for the treatment of asthma. PUBLIC HEALTH RELEVANCE: Asthma is a highly prevalent disease affecting 300 million patients worldwide, with 24 million in the United States including 10 million children, and its numbers appear to be increasing. Sadly, in spite of our best efforts to provide medical care, 5000 asthmatic patients die each year from their disease (about 100 per week). Clearly we need new and more effective treatments to control asthma, particularly severe asthma that includes acute life-threatening situations. This proposal is to test atotally novel approach, where COG compounds, which are peptide mimetics of apolipoprotein-E, confer profound anti-inflammatory activity, reduce airway hyperresponsiveness and reduce airway remodeling that is associated with the asthmatic condition in mousemodels. Based on the data collected in these proposed studies, we will be able to define how COG130 aerosols are tolerated in healthy mice and how they can reduce the signs and symptoms of disease in a house dust mite-induced model of asthma in mice. These studies are part of the foundation that we need to build to complete FDA required safety and toleratiblity studies in animals as a prelude to clinical testing in human asthmatic patients.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant We discovered that the SET oncoprotein is overexpressed in of biopsy samples from patients with hematological cancers and about of biopsy samples from patients with solid tumors Vitek et al US Patent and Also known as I PP A one of SETandapos s normal functions is to inhibit Protein Phosphatase A PP A Hahn showed that cancerous transformation of human cells required inhibition of PP A Of the known PP A inhibitors only SET has been reported to be druggable We discovered that apolipoprotein E apoE and the apoE mimetic peptide spanning residues specifically bound SET Fig Upon binding of apoE to SET cellular PP A activity levels increased supporting that apoE is a SET antagonist Fig andamp But most importantly the SET antagonist known as OP is also an apoE peptide mimetic that kills human cancer cells in vitro and in xenografted orthotopic tumors from both hematological and solid tumors Together these data strongly support that antagonism of SET is a useful target for anti cancer targeted drug development Since OP is an injectable peptide we propose a step screening cascade Figure to find orally active small molecule antagonists of SET that will permit re activation f PP A and the death of cancer cells In this Phase grant we will initiate Steps andamp of screening cascade We seek support in this proposal to use our High Throughput Screen HTS to find small molecule SET binders Hits from this HTS assay will then be subjected to an orthogonal assay where the toxicity of each hit to a cancer cell line and to a normal cell line wil be evaluated Additional orthogonal assays to further confirm the usefulness of hit compounds will be pursued in future applications Similar screens to find small molecules that disrupt protein protein interactions PPIs have for example yielded several small molecules including Nutlin a which disrupts p MDM binding The MDM disruptor AMG is about to start and Nutlin RG is currently in clinical trials where it has shown anti cancer activity in patients PUBLIC HEALTH RELEVANCE The nd leading cause of death in the US is from cancer Our research has uncovered a useful cancer target known as the andquot SET oncoprotein andquot SET normally inhibits the tumor suppressor known as Protein Phosphatase A PP A We have identified a peptide that binds to SET thereby inhibiting SETandapos s activity and allowing the PP A tumor suppressor to be re activated and kill the cancer cells In this proposal we are requesting support to begin the screening process to identify orally active small molecules that act like our peptide in binding to SET and allowing the PP A tumor suppressor to be re activated and kill the cancer cells These molecules are now called Phosphatse Activating Drugs or PADs and represent a new class of anti cancer drugs that complement and synergize with existing targeted kinase inhibitor drugs such as Gleevec


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2015

DESCRIPTION provided by applicant Alzheimerandapos s Disease AD is a progressive neuro degenerative disease that affects over million aged Americans and their million caregivers While the exact cause of AD in sporadic patients is unknown enzymes and proteins that increase in the AD state are logical targets for drug development Ornithine Decarboxylase ODC is the rate limiting enzyme for the synthesis of polyamines In addition to ODC itself levels of polyamines are also significantly increased in AD brains compared to age matched controls Polyamines have been associated with increased NMDA mediated excitotoxicity decreased inward rectifier activity and increased aggregation of the amyloid beta peptide A All of these activities can contribute to neuronal loss in the AD brain Difluoromethylornithine DFMO is an irreversible inhibitor of ODC that is off patent and has been shown to reduce brain levels of polyamines However gastrointestinal toxicities preclude dosing DFMO at high levels which is why DFMO is typically intravenously infused in patients with sleeping sickness We propose synthesizing novel prodrugs based upon the DFMO parent molecule that will be absorbed in the gut but do not cause gastrointestinal toxicities Once these prodrugs are in the blood stream esterases in the blood will cleave off the extra chemical groups to allow the DFMO inhibitor of ODC to circulate From our own experiments and those of others DFMO crosses the blood brain barrier to enter the brain and inhibit brain ODC In preliminary data we showed that administration of DFMO to the CVN mouse model of Alzheimerandapos s disease significantly improves their learning and memory behavior while reducing amyloid plaque like and neurofibrillary tangle like structures In addition another group recent reported similar therapeutic effects of DFMO administration in another mouse model of AD The extensive use of DFMO in humans with other diseases plus these new data support that prodrugs based on DFMO may be effective anti Alzheimerandapos s agents The prodrugs that we are proposing to synthesize are novel and pending successful testing for activity as detailed in this proposal wil be useful which are the two main criteria for patenting theses new compositions of matter and their field of use PUBLIC HEALTH RELEVANCE Orally Available Prodrugs for Alzheimerandapos s Disease AD AD is a progressive neuro degenerative disease that affects over million aged Americans and their million caregivers One enzyme that significantly increases in AD patients is ornithine decarboxylase or ODC ODC is the rate limiting enzyme in the production of polyamines which are also significantly increase in AD brains Polyamines enhance neuronal death in the brain where they contribute to neuronal death in AD We propose to create and test novel prodrugs that can be orally delivered to AD patients without gastrointestinal toxicities will reduce ODC activity will reduce polyamine levels and will reduce neuronal death in AD which should lead to improved learning and memory in AD patients


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 268.22K | Year: 2014

DESCRIPTION (provided by applicant): Over 24 million Americans suffer from asthma, which has become a chronic inflammatory disease of the airways characterized by reversible airflow obstruction and bronchospasm together with symptoms of wheezing, coughing,shortness of breath, and chest tightness. Unlike chronic obstructive pulmonary disease (COPD) or emphysema, airway obstruction is usually reversible in asthma, but if left untreated, can lead to irreversible air-flow obstruction due to airway remodeling.Treating asthma patients costs over 56 billion each year and typically consists of medications including bronchodilators that relax the smooth muscles in the airways and anti-inflammatories to reduce airway inflammation. In this proposal, we are focused on a potentially novel therapy for asthma: COG-compounds that antagonize inhibitor #2 of Protein Phosphatase 2A (I2PP2A or SET) leading to reactivation of PP2A and reduction of inflammation (Christensen et al. 2011). Recent literature by Levine and co


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.07K | Year: 2013

DESCRIPTION (provided by applicant): Diabetic peripheral neuropathy (DPN) is one of the most common and devastating complications of diabetes mellitus, affecting more than 50% of diabetic patients, and is the leading cause of foot amputation. DPN, characterized by peripheral axonal degeneration and demyelination, can be disabling and extremely painful, causing significant loss of functional abilities and decreasing quality of life. Currently, the only effectve treatments are glucose control and pain management. Although glucose control and some preventive strategies have been proposed to attenuate the development of DPN, none of them has demonstrated neuroreparative activity for existing neuropathy. Therefore, a neurorestorative strategy to repair damaged peripheral nerves is still critically needed to alleviate the persistent symptoms of established DPN. Cognosci has innovatively created and characterized a series of peptides derived from human apolipoprotein E (apoE), which we designate as COG compounds, from which we have identified a lead compound COG112 for inflammatory neurodegenerative diseases. Extensive studies have demonstrated that COG112 and other COG compounds exert potent neuroprotective activities against oxidative stress and inflammatory response, as well as neuroreparative activities both in vitro and in vivo. We have also obtained data showing that COG112 can significantly prevent axonal degeneration and promote axonal regeneration and remyelination in a sciatic nerve crush model. A similar neuroprotective effect has been validated in animal models of a variety of neurological disorders such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage and multiple sclerosis, implicating a therapeutic efficacy for these diseases. Because apoE has been considered as one of the genetic factors of diabetes and DPN, our preliminary data support that COG112 may demonstrate therapeutic efficacy on DPN by protecting peripheral nerves from hyperglycemia-mediated oxidative and inflammatory damages and promoting neuroregeneration. Therefore, we will test our hypothesis through both in vitro and in vivo models of DPN in the following specific aims: 1) To validate the potential neuroprotective effect of COG112 on a high glucose-induced neuronaldeath and axonal damage in primary dorsal root ganglion (DRG) cultures and the neuroregenerative effect on neurite outgrowth of DRGs from adult streptozocin (STZ)-induced diabetic rats. 2) To determine if COG112 exerts neuroprotective and neurorestorativeeffects in vivo by functional and histological examination in a DPN model of BKS db/db mice. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Our overall goal is to develop a novel neurorestorative therapy for diabetic neuropathy with not only protective potential, but also with reparative capability. Completion of this Phase I study will enable us to obtain proof of concept that apoE-mimetic COG112 can antagonize hyperglycemic oxidative stress, interfere with noxious inflammatory responses, andpromote axonal regeneration to maximize functional recovery. If substantiated by this study, COG112 may represent a first-in-class neurorestorative therapy for diabetic peripheral neuropathy that can satisfy this critically unmet medical need. The strategymay potentially be useful for other complications of diabetes such as diabetic retinopathy.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 273.24K | Year: 2013

DESCRIPTION (provided by applicant): Investigational Safety and Toxicity Studies of Subcutaneous COG1410 for Alzheimer's Disease: A Therapeutic Based upon Apolipoprotein-E That is Not Targeted to Amyloid-Beta Background on Alzheimer's Disease: Alzheimer'sDisease (AD) is the leading cause of dementia and 6th leading cause of death, affecting 5.4 million American patients and their 13 million caregivers. Unlike stroke, heart disease and other diseases whose deaths have been decreasing in recent years, from2000 to 2006, there was a 47% increase in deaths from AD. This increase shows no signs of stopping as the population of the US age 65 and older is projected to rise from 36 million in 2005 to 87 million by 2050, with a parallel rise in AD patients to 16 million by 2050. Medicare and Medicaid spend 148 Billion or about 20% of their combined programs on the care of AD patients, as there is no effective treatment, and family caregivers spent at least 94 Billion more on caring for relatives with AD. These data strongly support the enormous need to develop an effective anti-Alzheimer's therapeutic to not only reduce pain and suffering of patients and their families, but to also decrease the rapidly growing private and public debts incurred in providing healthcare for these Alzheimer's patients. Application of COG1410 to Alzheimer's Disease: Cognosci has developed an innovative series of neuroprotective and anti-inflammatory COG compounds, including COG1410, which are based upon the structure and activity of apolipoprotein-E-3. Our peer-reviewed publications show that these COG compounds specifically bind to SET, a known inhibitor of Protein Phosphatase 2A (PP2A). The formation of COG/SET complexes reduces SET's inhibitory action on PP2A thus permitting a re-activation so that levels of PP2A phosphatase activity increase in COG treated cells or animals (Christensen et al. 2011). While PP2A accounts for 70% of all phosphatase activity in the brain, the literature reports that SET levels are significantly increased in AD brains compared to age-matched healthy controls; and that the levels of PP2A phosphatase activity are significantly decreased in AD brains compared to age-matched healthy controls. To regain a healthy balance of SET and PP2A activities in the ADbrain, we propose that adding COG1410 will antagonize SET thereby permitting levels of PP2A enzyme activity to increase to healthy levels and to restore the brain to normal. Using our CVN-Alzheimer's mice, we demonstrated that subcutaneous administration of COG1410 resulted in decreased phospho-tau/neurofibrillary tangle-like pathology, decreased amyloid plaque-like pathology, and significantly improved learning and memory behaviors (Vitek et al. 2012a, Vitek et al. 2012b). Additional data provided in thisapplication show that all of these COG1410-mediated changes are significant in our CVN-Alzheimer's model. These data, together with many peer-reviewed publications on the actions of COG compounds in animal models, form the scientific basis for this translational proposal to bring COG1410 to the Alzheimer's population. Work Plan Overview: To translate COG1410 to the clinic and reduce the risks associated with commercialization (please see details in the attached proposal), we are proposing to perform allstudies necessary to receive approval of an Investigational New Drug (IND) application for subcutaneous administration of COG1410 for an Alzheimer's indication, followed by performance of Phase 1 human clinical trials. To achieve this goal, this Phase 1 SBIR application will perform the dose range finding studies with subcutaneously administered COG1410 in rats and dogs so as to determine the low, middle and high doses of SC-COG1410 that will be used in Phase 2 SBIR studies. Phase 2 SBIR studies will employlow, middle and high doses of SC-COG1410 on a daily basis for 28-days in definitive and GLP studies of pharmacokinetics and toxicokinetics in rats and dogs. The results of of these PK/TK studies, together with safety studies already completed, and GMP-synthesis, packaging and stability evaluations of COG1410, will be incorporated into an IND package and submitted to the FDA for approval. Once approved, then Phase2C/Phase 3-SBIR studies of clinical Phase 1A single ascending dose and Phase 1B repeat ascending dose studies of subcutaneous COG1410 in human subjects can be completed. With clinical studies showing that subcutaneous COG1410 can be safely given to human subjects, we will have achieved a significant milestone that reduces the risks and enables substantive commercialization activities to proceed. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Investigational Safety and Toxicity Studies of Subcutaneous COG1410 for Alzheimer's Disease: A Therapeutic Based upon Apolipoprotein-E That is NotTargeted to Amyloid-Beta Alzheimer's Disease (AD) is the leading cause of dementia and 6th leading cause of death, affecting 5.4 million American patients and their 13 million caregivers. Because there is no effective treatment, Medicare and Medicaid spend 148 Billion or about 20% of their combined programs on the


Patent
Cognosci, Inc. | Date: 2015-03-20

The present invention provides novel pharmaceutical compositions comprising ApoE-derived peptide dimers. In particular, the ApoE peptide dimers of the invention comprise at least two ApoE mimetic domains and can comprise one or more protein transduction domains. Methods of treating various conditions, such as cancer, inflammatory conditions, and neurodegenerative diseases, by administering the pharmaceutical compositions of the invention are also disclosed.

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