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#7 - A novel treatment for vascular disease/injury/inflammation in vasculature such as carotid artery which supplies blood to the brain
Short Title: Vascular Disease/Injury/Inflammation Therapeutics (potential prevention for stroke and Alzheimer’s disease)
Title: Human sRAGE Protein for Treating Vascular Disease, Injury, or Inflammation
NIH Reference No.: E-165-2011
Executive Summary
RAGE is a receptor which involves in multiple organ malfunction indications such as inflammation, tumor, Alzheimer’s disease, diabetic complications. Alzheimer’s disease is a neurodegenerative disease which inflicts more than 5 million Americans. The characteristic feature of Alzheimer’s disease includes senile plaques made up of beta amyloid deposits in the gray matter of the brain. RAGE transports circulating beta amyloid toxins across the blood brain barrier and into the brain, consequently, a RAGE antagonist, which regulates RAGE activity like the one in this invention, would potentially reduce the oxidative stress, inflammatory response and other activities associated with beta amyloid plaque accumulation.
Strokes occur when a blood vessel in or around the brain is blocked or ruptures. The type of stroke when a blood vessel is blocked by a blood clot or plaque is called ischemic stroke, which consists of 85% of total strokes. The type of stroke caused by trauma and vessel rupture is called hemorrhagic stroke, and accounts for about 15% of total strokes. More than 795,000 people in the U.S. have a stroke and impose about $36.5 billion of economic burden each year. Current methods of stroke prevention include maintaining a healthy life style, taking medications to control blood pressure and atrial fibrillation, as well as undergoing preventive medical procedures such as carotid artery surgery and angioplasty, to open up the narrowed blood vessels. However, these surgeries create extra injury to the blood vessels. Thus, a prophylaxis with minimal additional injury is needed.
The invention describes a method of producing an antagonist of RAGE which in addition to efficacy in treating vascular diseases potentially provides prophylaxis to stroke and Alzheimer’s diseases.
Scientific Progress
The inventors produced soluble RAGE in both insect Sf9 cells and Chinese hamster Ovary (CHO) cells and compared their bioactivity in cell assays and therapeutic efficacy in rat carotid artery balloon injury model (n=8-12). Compared with its insect cell produced counterpart, the soluble RAGE produced with CHO cells showed higher bioactivity in cell assays and reduction of neointimal growth and less inflammatory biomarkers using markedly reduced dose. The inventors also demonstrated that the N-glycoform modification from mammalian source is the key determinant for its bioactivity. The accumulated evidence suggests that glycobioengineering of soluble RAGE creates a significant for this therapeutic target.
Future Direction
Strengths
Weaknesses
Patent Status
US Application No. 61/582,574 filed in 2013
PCT Application No. PCT/US2013/020103 filed in 2013
Publication
Tae, H.J. et al. J of Molecular Medicine. 2013;91(12):1369-81 (PMID: 24132651)
Tae, H. J. Current Therapeutic Research 2014, in press.
Inventor Bio
Mark Talan, M.D., Ph.D. (recently retired)
Dr. Talan was trained as a physician at the First Leningrad Medical School in Russia. He received his Ph.D. in Physiology at the Pavlov Institute of Physiology in Russia where he continued to work as a principal researcher before coming to the NIA in 1980. His studies at the NIA in the area of thermoregulation, regulation of hemodynamics, and operant conditioning of autonomic functions evolved into his present interests of development and assessment of genetic therapeutic interventions in cardiovascular pathology using different experimental models.
Li Lin, Ph.D
Dr. Lin obtained her Ph.D. in biochemistry and molecular biology in State University of New York at Stony Brook (current Stony Brook University) and trained in Department of Immunobiology in Yale University as a Howard Hughes Medical Institute postdoctoral fellow, and in the Gladstone Institute of Virology and Immunology in University of California, San Francisco as a postdoctoral associate, and then staff scientist before joining the Graduate Program in Immunology in Johns Hopkins University School of Medicine as an assistant professor. Dr. Lin joined NIA as a guest researcher in 2005 before advancing as a Senior Research Fellow and then head of Receptor Unit of the Laboratory of Cardiovascular Sciences in 2010. Her work largely focuses on biochemistry and signaling mechanism of RAGE, therapeutic application of sRAGE, abd the role of RAGE/sRAGE action in aging and aging-related diseases.
Title: Human sRAGE Protein for Treating Vascular Disease, Injury, or Inflammation
NIH Reference No.: E-165-2011
Executive Summary
- Invention Type: Therapeutic
- Patent Status: US Application No. 61/582,574, PCT Application No. PCT/US2013/020103. US and PCT application filed in 2013, pending approval
- LINK: http://link.springer.com/article/10.1007%2Fs00109-013-1091-4
- NIH Reference Number: E-165-2011
- NIH Institute or Center: National Institute on Aging (NIA)
- Disease focus: Vascular Disease/Injury/Inflammation, for example, atherosclerosis and arterial restenosis. Potentially prevents stroke and Alzheimer’s Disease
- Basis of Invention: Protein
- How it works: Production of recombinant soluble receptors for an advanced glycation end products (RAGE) protein which acts as a decoy for a natural protein and blocks the pathogenic consequences associated with RAGE protein signaling
- Lead Inventors: Li Lin, Rui-ping Xiao, Wen Wei, Sungha Park, Mark Talan (NIA)
- Development Stage: Pre-clinical, in vivo animal model data available
- Novelty: Produce soluble RAGE (sRAGE) in mammalian cells and use of sRAGE containing mammalian post-translational modification for treatment of vascular disease and disorders
- Clinical Applications:
- Treats
- Screening for pharmacological compounds that may ameliorate the effects of acute brain trauma
- Testing materials capable of protecting cells from trauma, potentially identifying new materials that could be inserted into a helmet or otherprotective gear
- Identification of the best treatment and diagnostic path based on injury that has occurred in the emergency room, battlefield, blunt head trauma
- Prevents:
- Vascular inflammation
- Strokes by providing cardioprotection in acute myocardial infarction and ischemia
- Preventing/Treating Alzheimer’s Disease
RAGE is a receptor which involves in multiple organ malfunction indications such as inflammation, tumor, Alzheimer’s disease, diabetic complications. Alzheimer’s disease is a neurodegenerative disease which inflicts more than 5 million Americans. The characteristic feature of Alzheimer’s disease includes senile plaques made up of beta amyloid deposits in the gray matter of the brain. RAGE transports circulating beta amyloid toxins across the blood brain barrier and into the brain, consequently, a RAGE antagonist, which regulates RAGE activity like the one in this invention, would potentially reduce the oxidative stress, inflammatory response and other activities associated with beta amyloid plaque accumulation.
Strokes occur when a blood vessel in or around the brain is blocked or ruptures. The type of stroke when a blood vessel is blocked by a blood clot or plaque is called ischemic stroke, which consists of 85% of total strokes. The type of stroke caused by trauma and vessel rupture is called hemorrhagic stroke, and accounts for about 15% of total strokes. More than 795,000 people in the U.S. have a stroke and impose about $36.5 billion of economic burden each year. Current methods of stroke prevention include maintaining a healthy life style, taking medications to control blood pressure and atrial fibrillation, as well as undergoing preventive medical procedures such as carotid artery surgery and angioplasty, to open up the narrowed blood vessels. However, these surgeries create extra injury to the blood vessels. Thus, a prophylaxis with minimal additional injury is needed.
The invention describes a method of producing an antagonist of RAGE which in addition to efficacy in treating vascular diseases potentially provides prophylaxis to stroke and Alzheimer’s diseases.
Scientific Progress
The inventors produced soluble RAGE in both insect Sf9 cells and Chinese hamster Ovary (CHO) cells and compared their bioactivity in cell assays and therapeutic efficacy in rat carotid artery balloon injury model (n=8-12). Compared with its insect cell produced counterpart, the soluble RAGE produced with CHO cells showed higher bioactivity in cell assays and reduction of neointimal growth and less inflammatory biomarkers using markedly reduced dose. The inventors also demonstrated that the N-glycoform modification from mammalian source is the key determinant for its bioactivity. The accumulated evidence suggests that glycobioengineering of soluble RAGE creates a significant for this therapeutic target.
Future Direction
- Determine if a high dose of soluble RAGE produced in CHO cells will trigger adverse effects such as monocyte reaction in rat models
- Test the toxicity of soluble RAGE in chronic disease models by multiple administrations of low dose soluble RAGE, and monitor the impact on physiology and inflammatory response of the animal
- Repeat the therapeutic studies in different animal models for a broad coverage of multiple pathological conditions such as Alzheimer’s disease
Strengths
- Strong antagonist of RAGE with glycoform modification and is effective with a very low dose
- Antagonist for multi-ligand receptors which potentially treat a broad spectrum of pathological indications (including type 2 diabetes)
- Clear mechanism of action proven through a pilot study in a rat model which indicated the key component of bioactivity
- Potential longevity associated gene, highly interesting target
Weaknesses
- Only tested therapeutic efficacy immediately after acute vascular injury, not in chronic disease models.
- Need to use skull delivery method if future application requires blood brain barrier penetration, since the molecule is more than 40 KDa
- The inventor’s major focus is cardiovascular disease and thus collaboration with neurologists to test the therapeutic effects on brain is needed
Patent Status
US Application No. 61/582,574 filed in 2013
PCT Application No. PCT/US2013/020103 filed in 2013
Publication
Tae, H.J. et al. J of Molecular Medicine. 2013;91(12):1369-81 (PMID: 24132651)
Tae, H. J. Current Therapeutic Research 2014, in press.
Inventor Bio
Mark Talan, M.D., Ph.D. (recently retired)
Dr. Talan was trained as a physician at the First Leningrad Medical School in Russia. He received his Ph.D. in Physiology at the Pavlov Institute of Physiology in Russia where he continued to work as a principal researcher before coming to the NIA in 1980. His studies at the NIA in the area of thermoregulation, regulation of hemodynamics, and operant conditioning of autonomic functions evolved into his present interests of development and assessment of genetic therapeutic interventions in cardiovascular pathology using different experimental models.
Li Lin, Ph.D
Dr. Lin obtained her Ph.D. in biochemistry and molecular biology in State University of New York at Stony Brook (current Stony Brook University) and trained in Department of Immunobiology in Yale University as a Howard Hughes Medical Institute postdoctoral fellow, and in the Gladstone Institute of Virology and Immunology in University of California, San Francisco as a postdoctoral associate, and then staff scientist before joining the Graduate Program in Immunology in Johns Hopkins University School of Medicine as an assistant professor. Dr. Lin joined NIA as a guest researcher in 2005 before advancing as a Senior Research Fellow and then head of Receptor Unit of the Laboratory of Cardiovascular Sciences in 2010. Her work largely focuses on biochemistry and signaling mechanism of RAGE, therapeutic application of sRAGE, abd the role of RAGE/sRAGE action in aging and aging-related diseases.