SBIR-STTR Award

New therapeutic agents are urgently needed for the treatment of sickle cell disease (SCD), the world's most common genetic disease. Our long-term goal is to develop a botanical drug for use in children that prevents the inexorable progression of SCD. SCD affects approximately 100,000 people in the United States and millions worldwide. It kills more children in Africa than HIV, but while HIV commands vast attention from the international community, SCD is "virtually invisible." In the US, those with SCD have an average mortality in their 40s and an estimated aggregate cost of medical care in excess of $1.4 billion per year. In less developed countries, 80% of children with SCD die before the age of five. The only FDA approved disease-modifying drug for use in SCD is the anti-cancer drug hydroxyurea, which has serious side effects and is only approved for use in adults. SCD results from a mutation in the ¿-globin gene (Hb S), a variant of Hb A, the common adult hemoglobin. When deoxygenated, Hb S polymerizes, forming long polymers that deform the biconcave red blood cells (RBCs) into rigid, adherent, sickle-shaped cells. The rigid sickled RBCs are easily trapped in the microvasculature, blocking blood flow to tissues and organs with resultant ischemic tissue damage. Best supportive therapies for SCD include folic acid for anemia, penicillin to prevent infections, pneumococcal and influenza vaccinations, pain medication, and intravenous injection of fluids. Chronic transfusion therapy can modify the course of the disease, but hyperviscosity, alloimmune reaction, infection, and iron overload are just a few of the complications of transfusion therapy. Bone marrow transplants can cure SCD, but the morbidity and mortality of the procedure, coupled with difficulty in finding a donor match and the cost of the procedure, leave this an uncommon treatment option. We propose a Phase I dose escalation trial in adults with SCD to obtain an initial safety profile and explore possible effective oral doses of a botanical drug that inhibits RBCs from sickling. The rationale for the proposed research is that inhibiting RBCs from sickling, the hallmark of the disease, will reduce anemia, reduce vasoocclusion and pain, reduce cumulative organ damage, and reduce vascular inflammation caused by the adherence of the RBCs to endothelial and white blood cells.

Public Health Relevance:
This proposal supports development of a botanical to treat sickle cell disease in children. Sickle cell disease is an inherited blood disorder that affects ovr 100,000 persons in the U.S. Those affected often have high medical costs, a poor quality of life, and early death. The development of this drug addresses a critical unmet medical to treat this disease in children.

Project Terms:
Address; Adherence (attribute); Adult; Adverse effects; Affect; Africa; Age; Analgesics; Anemia; Animal Feed; Animals; Antineoplastic Agents; Attention; base; Biological Assay; Biological Markers; Blood flow; Body Weight; Bone Marrow Transplantation; Botanicals; Cell Shape; Cellular Structures; Cessation of life; Child; Chronic; Clinical Trials; Communities; cost; County Hospitals; Coupled; Data; Developing Countries; Development; Disease; Disease Progression; Domestic Animals; Dose; drug development; Drug usage; Eating; effective therapy; Erythrocytes; Event; FDA approved; Folic Acid; Funding; Genes; genotoxicity; Globin; Goals; Grant; Hematological Disease; Hemoglobin; Hereditary Disease; HIV; Human; hydroxyurea; Hyperviscosity; improved; In Vitro; in vivo; Infection; Infection prevention; Influenza vaccination; Inherited; International; intravenous injection; Iron Overload; Killings; Learning; Left; Legal patent; Leukocytes; Liquid substance; Manuscripts; Measures; Medical; Medical Care Costs; meetings; Molecular; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; Mutation; Neurocognitive; novel therapeutics; Oral; Organ; Organ failure; Oxygen; Pain; Pathogenesis; Penicillins; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; polymerization; Polymers; Preparation; prevent; Procedures; Process; Property; public health relevance; Quality of life; Rattus; Reaction; Renal function; Research; response; Safety; Sickle Cell; Sickle Cell Anemia; sickling; Signs and Symptoms; Small Business Innovation Research Grant; Sorghum (Plant); Spleen; stroke; Supportive care; Testing; Therapeutic Agents; Tissues; Toxic effect; Transfusion; Transgenic Organisms; Translating; United States; Variant; vascular inflammation; Venous blood sampling; Vulnerable Populations

New therapeutic agents are urgently needed for the treatment of sickle cell disease, the world's most common genetic disease. Our long-term goal is to develop a botanical drug (SCD- 101) for use in children and adults that slows or stops disease progression. Sickle cell disease affects approximately 100,000 people in the United States and millions worldwide. In the US, those with SCD have an average mortality in their 40s and an estimated aggregate cost of medical care in excess of $1.4 billion per year. In less developed countries, 80% of children with SCD die before the age of five. The only FDA approved disease-modifying drug for use in SCD is the anti-cancer drug hydroxyurea, which has serious side effects and is only approved for use in adults. Sickle cell disease results from a mutation in the β-globin gene (Hb S), a variant of Hb A, the common adult hemoglobin. When deoxygenated, Hb S polymerizes, forming long polymers that deform the biconcave red blood cells (RBCs) into rigid, adherent, sickle-shaped cells. The rigid sickled RBCs are easily trapped in the microvasculature, blocking blood flow to tissues and organs with resultant ischemic tissue damage. Best supportive therapies for SCD include folic acid for anemia, penicillin to prevent infections, pneumococcal and influenza vaccinations, pain medication, and intravenous injection of fluids. Chronic transfusion therapy can modify the course of the disease, but hyperviscosity, alloimmune reaction, infection, and iron overload are just a few of the complications of transfusion therapy. Bone marrow transplants can cure SCD, but the morbidity and mortality of the procedure, coupled with difficulty in finding a donor match and the cost of the procedure, leave this an uncommon treatment option. SCD-101 is being evaluated in a Phase 1B dose escalation trial in adults with sickle cell disease to obtain an initial safety profile and explore possible effective oral doses that inhibit RBCs from sickling. Early data shows that SCD-101 can inhibit RBC sickling in humans. To proceed to a Phase II clinical trial additional non-clinical studies are needed. This Phase II grant proposal is for funding the necessary non-clinical studies.

Public Health Relevance Statement:


Public Health Relevance:
This proposal supports elucidation of the mechanism of action of a botanical drug to treat sickle cell disease. Sickle cell disease is an inherited blood disorde that affects over 100,000 persons in the U.S. Those affected often have high medical costs, a poor quality of life, and early death. The development of this drug addresses a critical unmet medical to treat this disease.

NIH Spending Category:
Complementary and Alternative Medicine; Dietary Supplements; Hematology; Nutrition; Orphan Drug; Pain Conditions - Chronic; Pain Research; Patient Safety; Pediatric; Rare Diseases; Sickle Cell Disease

Project Terms:
Address; Adult; Adverse effects; Affect; Age; Ames Assay; Analgesics; Anemia; Animals; Antineoplastic Agents; Applications Grants; beta Globin; Bilirubin; Blood; Blood flow; Blood Vessels; Bone Marrow Transplantation; Botanicals; Caring; Cattle; Cell Shape; Cessation of life; Child; Chronic; Clinical; Clinical Trials; cohort; cost; Coupled; Data; Developing Countries; Development; Direct Costs; Disease; Disease Progression; Dose; drug development; Drug usage; Effectiveness; Embryonic and Fetal Development; Erythrocytes; FDA approved; flexibility; Folic Acid; Funding; Genes; Goals; Grant; Hemoglobin; Hereditary Disease; Human; hydroxyurea; Hyperviscosity; Hypoxia; In Vitro; in vivo; Infection; Infection prevention; Influenza vaccination; Inherited; intravenous injection; Iron Overload; Left; Life; Liquid substance; Marketing; Medical; Medical Care Costs; Monitor; Morbidity - disease rate; mortality; Mutation; Neurocognitive; Nitrogen; No-Observed-Adverse-Effect Level; novel therapeutics; Oral; Organ; Organ failure; Oryctolagus cuniculus; Pain; Participant; Pathogenesis; Patients; Penicillins; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Plant Leaves; Polymers; Price; Primary Health Care; Procedures; Prophylactic treatment; public health relevance; Quality of life; Rattus; Reaction; Renal function; Research; Rodent; Safety; safety study; Sales; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; sickling; Signs and Symptoms; Small Business Innovation Research Grant; Sorghum; Sorghum vulgare; Spleen; stroke; success; Supportive care; Teratology; Testing; Therapeutic Agents; Tissues; Toxic effect; Traditional Medicine; Transfusion; Translating; United States; Variant; Work