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RESEARCH TRIANGLE PARK, NC, United States

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: 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: 279.05K | Year: 2011

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory autoimmune disease in young adults, affecting more than 530,000 people in the United States and approximately 2 million worldwide. MS is characterized pathologically by inflammation, demyelination and axonal damage in the brain and spinal cord. In this disorder, the immune system mistakenly attacks the myelin sheath, which further damages surrounding nerves and eventually makes the patient wheelchair-bound. Current FDA-approveddisease-modifying treatments for MS, e.g., beta interferon 1a (Avonex(r) and Rebif(r)) and 1b (Betaseron(r)), glatiramer acetate (Copaxone(r)), mitoxantrone (Novantrone(r)) and newly marketed Tysabri(r) specifically target the inflammatory phase of the disease and have no clear effect on myelin repair. That more than half of MS patients do not respond well to existing treatments may be due, in part, to their failure to address the reparative component. Therefore, restoration of damaged axons and their surrounding myelin sheath, namely neuroregeneration and remyelination, may be more important than simple relief of the acute inflammatory atack when one is focused on long-term functional recovery. Cognosci has innovatively created a neurorestorative strategy based on the apolipoprotein E receptor-binding domain that can mimic the major bioactivities of apoE holo-protein and can be potentially used for treatment of related neurological disorders like MS. We have identified a lead compound, COG112, using multipleanimal models of human MS and have obtained proof-of- concept that the apoE-mimetic COG112 can properly attenuate inflammatory responses and facilitates myelin reconstruction, as well as axonal regeneration both in vitro and in vivo, indicating its potential utility for MS patients in the Clinic. To translate findings from lab bench to patient bedside, Cognosci will develop a clinically favorable dosing formulation that permits sustained release of the therapeutic compound. Successful development of a sustained release formulation will reduce the frequency of dosing and thus overcome the major limitation of frequent dosing typically needed for peptide therapeutics. The completion of the proposed studies is a critical step to validate this first-in-class remyelination therapy for MS in a more clinically favorable formulation that reduces the frequency of dosing. PUBLIC HEALTH RELEVANCE: Multiple Sclerosis is a devastating inflammatory autoimmune disease affecting half million young Americans. Uncontrolled progress of the disease usually put the victims on wheelchair for a life-ling time. Because MS is very complicated in etiology and pathology, the current MS drugs on the market only target on the inflammatory component of disease. Novel therapeutics is highly demanded. Cognosci has innovatively designed a compound, namely COG112, that had demonstrated multiple favorable properties for treatment of MS that can not only attenuate the inflammatory attack, but also stimulate the reconstruction of damaged myelin sheath as well as the reconnection of broken axons. The purpose of this proposal is to develop a sustained release formulation that permits extended release of therapeutic agent therefore reduces the need for frequent injection. This is a very important step from preclinical development towards clinical trials. Successful completion of this project will enable initiation of an IND safety/toxicity study to obtain FDA approval for clinical trial and is requisite for eventually bringing to clinic.


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.


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.

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