SBIR-STTR Award

The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2 diabetes mellitus, and mortality, and currently affects > 40% of US adults. MetS is associated with endothelial dysfunction, decreased circulating endothelial progenitor cells (EPCs), and a pro-inflammatory state. We have made the exciting discovery that therapy with allogeneic mesenchymal stem cells (MSCs) restores endothelial dysfunction and circulating EPCs towards normal the levels, and reduces markers of inflammation. Endothelial function represents a key driver of cardiovascular morbidity and mortality in MetS, and as such, restoring endothelial function could lead to clinical benefits in this patient population. We will conduct a clinical trial using Longeveron-produced allogeneic mesenchymal stem cells (LMSCs) delivered to subjects with MetS. In Phase I of this study, we will perform a dose-escalation Safety Run-In to first establish safety of LMSC therapy in subjects with MetS. After a safety review and approval from an independent data safety monitoring board (DMSB), Phase II of this Fast-Track Study will commence. This will entail a Randomized, Double-Blinded, Placebo-Controlled Phase on 40 subjects with MetS. The following specific aims will be examined. Specific Aim #1: To test the hypothesis that LMSCs are safe to intravenously-administer to subjects with MetS. We will examine for incidence of treatment-emergent serious adverse events (TE-SAEs); blood chemistry, hematology, coagulation, and urinalysis; and alloimmune reaction and T and B cell subsets to examine levels of immune activation. Specific Aim #2: To test the hypothesis that intravenously-administered LMSCs will improve endothelial dysfunction and increase circulating EPCs in subjects with MetS. We will examine endothelial dysfunction using flow-mediated vasodilation (FMD), and circulating EPCs by colony assays and flow cytometry. Specific Aim #3: To test the hypothesis that intravenously-administered LMSCs will improve systemic markers of inflammation in subjects with MetS. We will use ELISA to examine panels of inflammatory markers. Specific Aim #4: To test the hypothesis that intravenously-administered LMSCs will lead to clinical improvement in subjects with MetS. We will examine for changes in glucose control (hemoglobin A1c, fasting glucose, fasting insulin, HOMA), lipid profile (HDL, LDL, triglycerides, cholesterol), blood pressure and cardiac function, physical performance, and subject quality of life. We anticipate that the results of this study will lead to a much needed therapeutic for subjects with MetS. Longeveron is positioned to rapidly advance this program to a pivotal phase III trial if the results prove positive, and to bring this technology to market.

Public Health Relevance Statement:
The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2 diabetes mellitus, and mortality. MetS currently affects over 40% of US adults, and has reached epidemic proportions worldwide; yet highly effective treatments are not available. In this study, a clinical trial will be conducted in which we will use cell therapy to treat MetS (www.ClinicalTrials.gov: identifier NCT02587572). This therapeutic is unique in that it targets 3 major contributors to MetS (endothelial dysfunction, diminished endothelial progenitor cells, and increased inflammation), and we anticipate will provide a highly effective and much needed treatment for MetS.

Project Terms:
Address; Adult; Affect; Allogenic; Anti-inflammatory; Anti-Inflammatory Agents; B-Lymphocyte Subsets; Biological Assay; Blinded; Blood Chemical Analysis; blood glucose regulation; Blood Pressure; Cardiac; cardiovascular disorder risk; Cardiovascular system; Cell Therapy; Cells; Cholesterol; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Coagulation Process; Controlled Clinical Trials; cytokine; Dobutamine; Dose; Double-Blind Method; effective therapy; endothelial dysfunction; Enzyme-Linked Immunosorbent Assay; Epidemic; Fasting; fasting glucose; Female; Fibrin fragment D; Fibrinogen; Flow Cytometry; follow-up; Glucose; Glycosylated hemoglobin A; Health Surveys; Hematology; High Density Lipoproteins; immune activation; improved; Incidence; indexing; Individual; Inflammation; Inflammatory; inflammatory marker; Infusion procedures; insight; Insulin; Interleukin-1; Interleukin-6; International; Intravenous; Lead; Lipids; low density lipoprotein triglyceride; male; Measurement; Measures; Mediating; Mesenchymal Stem Cells; Metabolic syndrome; Modeling; Monitor; Morbidity - disease rate; mortality; multipotent cell; Non-Insulin-Dependent Diabetes Mellitus; patient population; Phase; phase 1 study; phase III trial; Physical Performance; Placebo Control; Placebos; Positioning Attribute; programs; Property; Quality of life; Questionnaires; Randomized; Reaction; Reading; Risk; Running; Safety; Sampling; Serious Adverse Event; Serum; SF-36; Stem cells; Stress; Study Subject; T-Lymphocyte; Technology; Testing; Therapeutic; TNF gene; Urinalysis; Urine; Vasodilation; Walking

The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2 diabetes mellitus, and mortality, and currently affects > 40% of US adults. MetS is associated with endothelial dysfunction, decreased circulating endothelial progenitor cells (EPCs), and a pro-inflammatory state. We have made the exciting discovery that therapy with allogeneic mesenchymal stem cells (MSCs) restores endothelial dysfunction and circulating EPCs towards normal the levels, and reduces markers of inflammation. Endothelial function represents a key driver of cardiovascular morbidity and mortality in MetS, and as such, restoring endothelial function could lead to clinical benefits in this patient population. We will conduct a clinical trial using Longeveron-produced allogeneic mesenchymal stem cells (LMSCs) delivered to subjects with MetS. In Phase I of this study, we will perform a dose-escalation Safety Run-In to first establish safety of LMSC therapy in subjects with MetS. After a safety review and approval from an independent data safety monitoring board (DMSB), Phase II of this Fast-Track Study will commence. This will entail a Randomized, Double-Blinded, Placebo-Controlled Phase on 40 subjects with MetS. The following specific aims will be examined. Specific Aim #1: To test the hypothesis that LMSCs are safe to intravenously-administer to subjects with MetS. We will examine for incidence of treatment-emergent serious adverse events (TE-SAEs); blood chemistry, hematology, coagulation, and urinalysis; and alloimmune reaction and T and B cell subsets to examine levels of immune activation. Specific Aim #2: To test the hypothesis that intravenously-administered LMSCs will improve endothelial dysfunction and increase circulating EPCs in subjects with MetS. We will examine endothelial dysfunction using flow-mediated vasodilation (FMD), and circulating EPCs by colony assays and flow cytometry. Specific Aim #3: To test the hypothesis that intravenously-administered LMSCs will improve systemic markers of inflammation in subjects with MetS. We will use ELISA to examine panels of inflammatory markers. Specific Aim #4: To test the hypothesis that intravenously-administered LMSCs will lead to clinical improvement in subjects with MetS. We will examine for changes in glucose control (hemoglobin A1c, fasting glucose, fasting insulin, HOMA), lipid profile (HDL, LDL, triglycerides, cholesterol), blood pressure and cardiac function, physical performance, and subject quality of life. We anticipate that the results of this study will lead to a much needed therapeutic for subjects with MetS. Longeveron is positioned to rapidly advance this program to a pivotal phase III trial if the results prove positive, and to bring this technology to market.

Public Health Relevance Statement:
The metabolic syndrome (MetS) is a cluster of factors that increases the risks for cardiovascular disease, type 2 diabetes mellitus, and mortality. MetS currently affects over 40% of US adults, and has reached epidemic proportions worldwide; yet highly effective treatments are not available. In this study, a clinical trial will be conducted in which we will use cell therapy to treat MetS (www.ClinicalTrials.gov: identifier NCT02587572). This therapeutic is unique in that it targets 3 major contributors to MetS (endothelial dysfunction, diminished endothelial progenitor cells, and increased inflammation), and we anticipate will provide a highly effective and much needed treatment for MetS.

NIH Spending Category:
Aging; Biotechnology; Cardiovascular; Clinical Research; Clinical Trials and Supportive Activities; Diabetes; Patient Safety; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation

Project Terms:
Address; Adult; Affect; Allogenic; Anti-inflammatory; B-Lymphocyte Subsets; Biological Assay; Blinded; Blood Chemical Analysis; blood glucose regulation; Blood Pressure; cardiovascular disorder risk; Cardiovascular system; Cell Therapy; Cells; Cholesterol; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Coagulation Process; Controlled Clinical Trials; cytokine; Dobutamine; Dose; Double-Blind Method; effective therapy; endothelial dysfunction; Endothelium; Enzyme-Linked Immunosorbent Assay; Epidemic; Fasting; fasting glucose; Female; Fibrin fragment D; Fibrinogen; Flow Cytometry; follow-up; Glucose; Glycosylated hemoglobin A; Health Surveys; heart function; Hematology; High Density Lipoproteins; immune activation; improved; Incidence; indexing; Individual; Inflammation; Inflammatory; inflammatory marker; Infusion procedures; insight; Institutional Review Boards; Insulin; Interleukin-1; Interleukin-6; International; Intravenous; Lead; Lipids; low density lipoprotein triglyceride; male; Measurement; Measures; Mediating; Mesenchymal Stem Cells; Metabolic syndrome; Modeling; Monitor; Morbidity - disease rate; mortality; multipotent cell; Multipotent Stem Cells; Non-Insulin-Dependent Diabetes Mellitus; participant safety; patient population; Phase; phase 1 study; phase III trial; Physical Performance; Placebos; Positioning Attribute; programs; Property; Quality of life; Questionnaires; Randomized; Reaction; Reading; Risk; Running; Safety; Sampling; Serious Adverse Event; Serum; SF-36; stem cell therapy; Stem cells; Stress; Study Subject; T-Lymphocyte; Technology; Testing; Therapeutic; TNF gene; Urinalysis; Urine; Vasodilation; Walking