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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


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.


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.


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

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