The purpose of this study is to establish in vivo proof of principle for a human therapeutic for hematopoietic stem cell regeneration in the bone marrow after myeloablation from radiation. Blood stem cells are the most susceptible to the effects of radiation and the most lethal. We have already demonstrated proof of principle for our therapeutic in vitro. If successful, the product of this project will be a protein-based drug that ill stimulate the growth of bone marrow cells and prevent death in people exposed to radiation. There is no drug or treatment available that stimulates the production of hematopoietic stem cells; Epogen and G-CSF only skew the differentiation of the existing pool of stem cells toward red blood cells or white blood cells, respectively. In addition, the FDA recently issued a Black Box warning that the use of these and related drugs increases risk of cancer recurrence. Our therapeutic is a novel growth factor that we discovered is secreted by 'naîµ¥' state human stem cells and is the only growth factor or cytokine required for human pluripotent stem cell growth. To date, we are the only group that has been able to revert and maintain genetically unmodified human stem cells in this elusive state, so were uniquely positioned to discover this growth factor, to identify and make its active form and to discover its target. The novel growth factor is essentially not expressed in adult tissue. However, its target growth factor receptor is expressed on bone marrow hematopoietic stem cells and on cancer cells, albeit in slightly different forms. To address the potential risk of stimulating cancerous growth, we have also identified a monoclonal antibody that mimics the stimulatory function of our growth factor, but importantly does not recognize the target receptor as it appears on cancer cells. Our approach is to irradiate healthy mice to 7- Gy, which kills 90% of untreated mice Day 12-15. Treated mice will receive either the protein growth factor or the monoclonal antibody once daily by ip injection. We have an animal team that routinely performs mouse experiments testing our anti-cancer Fabs. By Day 19, 30% or greater survival indicates effectiveness of our agent. After sacrifice, peripheral and bone marrow blood will be analyzed to determine the extent of recovery that has taken place. Ideal is 80% recovery by Day 19. We will then test the effect of our candidate therapeutic monoclonal antibody on animals bearing human tumors. The drug we develop would benefit related fields of defense strategies following nuclear attack, HSC growth in vitro, and development of anti-cancer drugs that have no effect on bone marrow or stem cells.
Thesaurus Terms: Address;Adult;Affect;Am 80;Animals;Anti-Cancer Therapeutic;Antineoplastic Agents;Assault;Base;Biometry;Blood;Blood Banks;Blood Cell Count;Blood Cells;Blood Circulation;Bone Marrow;Bone Marrow Cells;Bone Marrow Purging;Bone Marrow Stem Cell;Bone Marrow Transplantation;Boxing;Cancer Cell;Cancer Recurrence;Cancer Risk;Cancer Stem Cell;Cancer Therapy;Cancerous;Cell Growth;Cells;Cessation Of Life;Chemotherapy;Control Groups;Csf3 Gene;Cytokine;Development;Disease;Dose;Du145;Effectiveness;Engineering;Engraftment;Epoetin Alfa;Erythrocytes;Exposure To;Goals;Growth;Growth Factor;Growth Factor Receptors;Health;Hematopoietic Stem Cells;Human;Human Stem Cells;Immune;In Vitro;In Vivo;Induced Pluripotent Stem Cell;Injection Of Therapeutic Agent;Killings;Left;Leukemia;Leukocytes;Life;Malignant Neoplasms;Mammary Neoplasms;Mediating;Monoclonal Antibodies;Mortality Vital Statistics;Mucin-1 Staining Method;Mus;Natural Regeneration;Nme1 Gene;Novel;Novel Therapeutics;Nuclear;Patients;Pc3 Cell Line;Peripheral;Persons;Pharmaceutical Preparations;Pluripotent Stem Cells;Positioning Attribute;Prevent;Production;Prostatic Neoplasms;Proteins;Protocols Documentation;Radiation;Radiation Effect;Reagent;Receptor;Reconstitution;Recovery;Research Study;Risk;Stem;Stem Cells;T47d;Testing;Therapeutic;Therapeutic Monoclonal Antibodies;Tissues;Transplantation;Tumor;Tumor Growth;Work
