SBIR-STTR Award

A clinical need exists for better osteoporosis treatments since only one anabolic therapy (recombinant human parathyroid hormone) is commercially available. Bears are uniquely able to prevent bone loss during physical inactivity (hibernation) by maintaining balanced bone remodeling; the biological processes behind this phenomenon are likely governed by endogenous parathyroid hormone (PTH), since serum PTH levels are correlated with the bone formation marker osteocalcin in hibernating and active bears. Thus, our goal is to investigate the anabolic effects of bear PTH in comparison to human PTH to aid in the development of a more effective anabolic treatment for osteoporosis. It is possible to upregulate anabolic pathways in bone cells by changing PTH's amino acid sequence. Bear PTH has eleven differences in its amino acid sequence compared to human PTH. Thus, bear PTH may promote a greater anabolic response in bone than human PTH by decreasing osteoblast apoptosis and increasing bone matrix production by altering gene expression. We propose to recombinantly produce bear PTH 1-84 and measure its ability to promote bone formation in vitro by measuring bear PTH's effects on apoptosis and gene expression in bone cells (MC-3T3 osteoblastic cells). The cellular responses will be compared with the effects of recombinant human PTH 1-84 to determine the relative anabolic potential of bear PTH. We will also treat rats with daily subcutaneous injections of human PTH 1-84 and bear PTH 1-84. Femoral bone strength will be determined by 3-point bending tests and vertebral bone strength by compression tests. Bone formation rate will be quantified histologically in calcein labeled bone tissue, mineral content will be determined by ashing, and geometry (e.g., cross- sectional area) will be quantified by image analysis techniques. PUBLIC HEALTH RELEVENCE: Improved drug therapies are needed to treat the approximately 44 million Americans affected by osteoporosis. Bears uniquely prevent osteoporosis during physical inactivity (hibernation) through biological processes regulated by parathyroid hormone (PTH). Injections of human PTH are currently used to rebuild bone in severely osteoporotic patients, but due to its different protein structure, bear PTH may cause greater bone formation than human PTH, and therefore may be a more effective treatment for human osteoporosis.

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Project Summary/Abstract. A clinical need exists for better osteoporosis treatments since only one anabolic therapy (truncated recombinant human parathyroid hormone 1-34, teriparatide/Forteo(R)) is commercially available. Bears possess the unique ability to prevent bone loss during physical inactivity (hibernation) by maintaining balanced bone remodeling;the biological processes behind this phenomenon are likely governed by endogenous parathyroid hormone (PTH), since serum PTH levels are correlated with the bone formation marker osteocalcin in hibernating and active bears. Thus, our goal is to investigate the anabolic effects of Black Bear (BB)- PTH 1-84 to aid in the development of a more effective anabolic treatment for osteoporosis. It is possible to up-regulate anabolic pathways in bone cells by altering the amino acid sequence of PTH. BB-PTH 1-84 has nine differences in its amino acid sequence compared to full length human PTH. Thus, BB-PTH 1-84 may promote a greater anabolic response in bone than human PTH by decreasing osteoblast apoptosis and increasing bone matrix production by altering gene expression. In Phase I work we recombinantly produced BB-PTH 1-84 and found it is significantly more potent at increasing bone mass and strength in healthy male mice. In the Phase II work we will perform a dose-response study in ovariectomized mice to evaluate the efficacy of bear PTH 1-84 at reversing ovariectomy induced bone loss. We will also treat human osteoblastic cells with human PTH 1-84 and BB-PTH 1-84 to compare their abilities to activate anabolic bone cell responses by activating the human PTH receptor. Importantly, non-GLP and GLP pathology/toxicology studies will be performed with Phase II STTR funding in order to enable the Company to file an IND with the FDA to initiate future Phase I/II clinical studies in patients with documented osteoporosis. , ,

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Project narrative:
Improved drug therapies are needed to treat the approximately 44 million Americans affected by osteoporosis. Bears uniquely prevent osteoporosis during physical inactivity (hibernation) through biological processes regulated by parathyroid hormone (PTH). Injections of human PTH are currently used to rebuild bone in severely osteoporotic patients, but due to its different amino acid sequence, BB-PTH 1-84 may elicit greater bone formation than human PTH, and therefore may be a more effective treatment for human osteoporosis.

Thesaurus Terms:
3'5'-Cyclic Ester Of Amp;4-Carboxyglutamic Protein, Bone;Adenosine Cyclic 3',5'-Monophosphate;Adenosine Cyclic Monophosphate;Adenosine, Cyclic 3',5'-(Hydrogen Phosphate);Affect;American;Amino Acid Sequence;Amino Acids;Anabolic Agents;Animal Model;Animal Models And Related Studies;Apopain;Apoptosis;Apoptosis Pathway;Apoptotic;Assay;Attenuated;Bears;Bioassay;Biologic Assays;Biological;Biological Assay;Biological Function;Biological Process;Bisphosphonates;Black Bear;Blood Serum;Bone;Bone Formation;Bone Matrix;Bone And Bones;Bone Gamma-Carboxyglutamic Acid Protein;Bone Remodeling;Bones And Bone Tissue;Casp-3;Casp3;Cpp-32;Cpp32;Cpp32 Protein;Cpp32b;Cpp32beta;Calcium-Binding Protein, Vitamin K-Dependent;Canine Species;Canis Familiaris;Caspase 3, Apoptosis-Related Cysteine Protease;Cell Communication And Signaling;Cell Death, Programmed;Cell Signaling;Cells;Chronic;Clinical;Clinical Research;Clinical Study;Common Rat Strains;Cyclic Amp;Cysteine Protease Cpp32;Data;Development;Dogs;Dose;Drug Therapy;Drugs;Equilibrium;Fda Approved;Fos Gene;Female;Forteo;Fracture Due To Osteoporosis;Funding;Future;G0s7;Gene Expression;Gla Protein, Bone;Goals;Hibernation;Hour;Human;Human Parathyroid Hormone (1-34);Human, General;In Vitro;Incubated;Injection Of Therapeutic Agent;Injections;Intracellular Communication And Signaling;Length;Mammals, Dogs;Mammals, Mice;Mammals, Rats;Man (Taxonomy);Man, Modern;Medication;Mesenchymal Progenitor Cell;Mesenchymal Stem Cells;Mice;Murine;Mus;Oophorectomy;Osteoblasts;Osteocalcin;Osteogenesis;Osteoporosis;Osteoporosis With Fracture;Osteoporosis, Post-Menopausal;Osteoporosis, Postmenopausal;Osteoporotic Fracture;Ovariectomy;Parp Cleavage Protease;Pth (1-84);Pth Protein, Human;Pth-Pthrp Receptor;Pth-Related Peptide Receptor;Pth-Related Protein Receptor;Pthlp Receptor;Pthrp Receptor;Parathyroid Hormone;Parathyroid Hormone (1-84);Parathyroid Hormone Peptide (1-34);Parathyroid Hormone Receptor;Parathyroid Hormone Receptor 1;Parathyroid Hormone Receptor Type I;Parathyroid Hormone Receptors;Parathyroid Hormone-Related Peptide Receptor;Parathyroid Hormones;Pathology;Pathway Interactions;Patients;Peptides;Perimenopausal Bone Loss;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacotherapy;Phase;Physical Activity;Population;Postmenopausal Bone Loss;Postmenopausal Osteoporosis;Production;Protein Structure, Primary;Protooncogene Fos;Rat;Rattus;Receptor, Parathyroid Hormone, Type 1;Receptor, Parathyroid Hormone-Like Peptide;Recombinants;Relative;Relative (Related Person);Research;Risk;Sca-1;Srebp Cleavage Activity 1;Sttr;Safety;Serum;Signal Transduction;Signal Transduction Systems;Signaling;Small Business Technology Transfer Research;Starvation;Structure;Subcutaneous Injections;Teriparatide;Testing;Toxicology;United States;Ursidae;Ursidae Family;Ursus;Vitamin K-Dependent Bone Protein;Work;Yama;Yama Protein;Abstracting;Adenosine 3'5' Monophosphate;Aminoacid;Balance;Balance Function;Biological Signal Transduction;Biphosphonate;Bisphosphonate;Bone;Bone Cell;Bone Loss;Bone Mass;Bone Remodelling;C Fos;C-Fos Gene;C-Fos Proto-Oncogenes;Camp;Canine;Caspase-3;Cysteine Protease P32;Diphosphonate;Domestic Dog;Drug Development;Drug/Agent;Effective Therapy;Female Gonadectomy;Hpth (1-34);Hpth(1-84);Human Pth Protein;Improved;In Vivo;Indexing;Interest;Male;Mineralization;Model Organism;Mouse Model;Novel;Osteoporosis With Pathological Fracture;Parathormone;Parathyroid Hormone, Human;Pathway;Prevent;Preventing;Protein Sequence;Public Health Relevance;Response;Safety Study;Subcutaneous;Substantia Spongiosa;Substantia Trabecularis;Trabecular Bone;V-Fos Fbj Murine Osteosarcoma Viral Oncogene Homolog