Cortisol is a steroid hormone that regulates a wide range of processes throughout the body, including metabolism and the immune response. It also has a very important role in helping the body respond to stress. High levels of adrenocorticotropic hormone (ACTH) in the adrenal glands stimulate the secretion of cortisol, causing blood levels of cortisol to rise. Too much cortisol for a long period of time leads to a condition called Cushingâs syndrome, characterized by rapid weight gain mainly in the face, chest and abdomen contrasted with slender arms and leg, a flushed and round face, high blood pressure, osteoporosis, skin changes, muscle weakness, mood swings that show as anxiety, depression or irritability and increased thirst and frequency of urination. When Cushingâs syndrome is caused by a tumor of the pituitary gland that secretes too much ACTH, the condition is known as Cushingâs disease. For reasons that are unclear, Cushingâs disease affects women more often than men by almost 3 to 1. Women with Cushingâs disease may experience irregular menstruation and have excessive hair growth on their face, abdomen, and legs. Left untreated, Cushingâs disease can be deadly, and the preferred course of action is to surgically remove the tumor without damaging the rest of the pituitary gland. When surgery is not possible or fails to completely remove the tumor, medication is often needed to block the effects of the excess cortisol. While steroid synthesis inhibitors, glucocorticoid receptor blockers, cabergoline, and somatostatin analogs have certainly made a great difference in the care of patients with Cushingâs disease, a substantial number of these patients are never adequately treated. There is a clear unmet medical need for novel treatments with better control of the disease and fewer side effects. We propose an antibody therapeutic as a novel approach to controlling excess cortisol that we believe can act across the entire patient population and that can work in concert with other medications. Our goal for this SBIR NIH grant is to initiate the necessary development work to make this new medicine possible.
Public Health Relevance Statement: While steroid synthesis inhibitors, glucocorticoid receptor blockers, cabergoline, and somatostatin analogs have made a great difference in the care of patients with Cushingâs disease, a substantial number of these patients are never adequately treated. There are a handful of new treatments on the horizon, but most are âme-tooâ drugs that are unlikely to be more effective than what is currently available. We are proposing a novel antibody approach to treating Cushingâs disease across the entire spectrum of the patient population.
Project Terms: Abdomen; Address; Adrenal Cortex; Adrenal Gland Hyperfunction; Adrenal Glands; Adrenalectomy; Affect; Affinity; alpha-Melanocyte stimulating hormone; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Anxiety; arm; Bilateral; Binding; Biological; Biological Assay; Blood; cabergoline; Carrier Proteins; Cell Line; cell type; Chest; Circadian Rhythms; Corticotropin; Corticotropin Receptors; cross reactivity; Cushing Syndrome; design; Desire for food; Development; disorder control; drug candidate; Endocrine System Diseases; energy balance; Epitopes; Exocrine pancreas; experience; Face; Flushing; Frequencies; Glucocorticoid Receptor; Glucocorticoids; Goals; Grant; Growth; Hair; Human; Hybridomas; Hydrocortisone; Hypertension; Immune response; Immunization; Immunoglobulins; In Vitro; in vivo; Individual; inhibitor/antagonist; innovation; Intervention; Irregular Menstruation; lead candidate; lead optimization; Left; Leg; Length; Libraries; Life; Literature; Lymphoid Tissue; manufacturability; Medical; Medicine; melanocortin receptor; men; Mental Depression; Metabolism; Mission; Modeling; Moods; Mouse Strains; Muscle Weakness; Neuropeptides; novel; novel strategies; Operative Surgical Procedures; Osteoporosis; Parents; Patient Care; patient population; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Pituitary Diseases; Pituitary Gland; Pituitary Neoplasms; Pituitary-dependent Cushing's disease; Plant Roots; polyclonal antibody; polyclonal human antibody; polypeptide; pre-clinical; preclinical efficacy; Pro-Opiomelanocortin; Process; Production; Property; protein aminoacid sequence; Protocols documentation; Rat Strains; receptor; Recombinants; Rest; Role; screening; Serum; side effect; Skin; Skin Pigmentation; Small Business Innovation Research Grant; Solvents; somatostatin analog; Specificity; Steroid biosynthesis; steroid hormone; Steroids; Stress; Structure; Testing; Therapeutic antibodies; Therapeutic Monoclonal Antibodies; Thirst; Time; Toxicity Tests; Transgenic Mice; tumor; United States National Institutes of Health; Urination; Validation; Wei
