US20130096061A1 - Method of treating skeletal dysplasias using vessel dilator - Google Patents

Method of treating skeletal dysplasias using vessel dilator Download PDF

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US20130096061A1
US20130096061A1 US13/693,372 US201213693372A US2013096061A1 US 20130096061 A1 US20130096061 A1 US 20130096061A1 US 201213693372 A US201213693372 A US 201213693372A US 2013096061 A1 US2013096061 A1 US 2013096061A1
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vessel dilator
cnp
natriuretic peptide
administered
proliferation
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David Lynn Vesely
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University of South Florida
US Department of Veterans Affairs VA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to treatment of skeletal and osteopathic disorders. Specifically, the invention provides for the stimulation of bone growth using vessel dilator.
  • CNP C-natriuretic peptide
  • natriuretic peptides with short half-lives such as CNP and atrial natriuretic peptide (ANP) can regulate proliferation and differentiation of osteoblasts and chondrocytes
  • CNP and atrial natriuretic peptide ANP
  • atrial natriuretic peptide ANP
  • cGMP produced in response to ANP and CNP regulates proliferation and differentiation of osteoblastic cells.
  • Cartilage-specific overexpression of CNP partially rescues the achondroplasia dwarfism of the CNP-deficient mice, suggesting that CNP stimulates bone growth through direct effects on chondrocytes (Yasoda A, et al. 2004 Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80-86). Contrarily, mice with overexpression of CNP in cartilage have prominent skeletal overgrowth (Yasoda A, et al. 2004 Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80-86).
  • CNP C-type natriuretic peptide
  • NPR natriuretic peptide
  • CNP and ANP are ring-structured natriuretic peptides with very short half-lives of ⁇ 3 min in the circulation (Kalra P R, et al. 2001 The role of C-natriuretic peptide in cardiovascular medicine. Eur Heart J 22:997-1007, Teixeira C C, et al. 2008 Nitric oxide, C-type natriuretic peptide and cGMP as regulators of endochondral ossification. Dev Biol 319:171-178; Nakao K, et al. 1986 The pharmacokinetics of ⁇ -human natriuretic polypeptide in healthy subjects.
  • compositions currently used for treatment of skeletal disorders have a short-lived in vivo residence. It would therefore be beneficial to develop longer-lived compounds, facilitating fewer treatments with improved effect.
  • Vessel dilator has biologic effects that last 12-times longer than CNP, ANP or BNP as above which makes it unique and preferable for therapy as with its longer half-life it can be given less frequently for treatment. Because vessel dilator is a natriuretic peptide hormones with similar cGMP mechanism of action but much longer biologic effects than CNP or ANP (Kalra P R, et al. 2001 The role of C-natriuretic peptide in cardiovascular medicine. Eur Heart J 22:997-1007; Teixeira C C, et al. 2008 Nitric oxide, C-type natriuretic peptide and cGMP as regulators of endochondral ossification.
  • Circulation 90:1129-1140 it was determined that a natriuretic peptide with at least 12-fold longer biologic effects (Vesely D L, et al. 1994 Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans. Circulation 90:1129-1140) increased osteoblasts' proliferation such as CNP. Vessel dilator and CNP were compared directly against each other in dose response curves to determine their comparative ability to enhance osteoblast proliferation.
  • vessel dilator stimulated the proliferation of osteoblasts, which results in the formation of new bone.
  • Vessel dilator exhibited biologic effects 12 times longer than CNP, ANP, or BNP.
  • vessel dilator was used to treat skeletal disorders in patients.
  • vessel dilator is administered at a concentration of between 10 pM and 10 nM, including 1 nM, 100 pM, and 10 pM.
  • Appropriate concentrations of vessel dilator for administration may be be calculated in pg and/or ng/kg body weight for infusion by dividing the desired concentration in molarity by vessel dilator's known molecular weight of 3878.31. For example, dividing 100 ⁇ M by the molecular weight provides an administration amount of 0.026 pg/kg.
  • Vessel dilator and C-natriuretic peptide were compared directly against each other in dose-response curves to determine their comparative ability to enhance osteoblast proliferation, with vessel dilator exhibiting better results than CNP.
  • Vessel dilator was found to stimulate osteoblasts at 1000-lower concentrations than CNP, and possess biologic effects that last longer than 6 hours compared to less than 30 minutes for CNP, ANP and BNP. This permits vessel dilator to be administered 4 times per day, such as about every 6 hours or at every 6 hours.
  • cardiac hormone vessel dilator is useful for the treatment of achondroplastic dwarfs and other skeletal dysplasias.
  • skeletal disorders that are treatable with the present invention include achondroplasia skeletal dysplasias and other dysplasias, short stature, osetopenia, osteoporosis, osteomalacia, hypoparathyroidism, tumor associated osteomalacia, rickets, osteogenesis imperfecta, osteitis fibrosa cystic secondary to hyperparathyroidism, Paget's Disease, and osteitis deformans, short stature, and osteoporosis.
  • osteoporosis is a common disease in adults with current treatments such as biphosphonates, parathyroid hormone, calcitonin and 1,25-dihydroxy vitamin D all working via inhibiting osteoclasts.
  • Current treatment for osteoporosis inhibits the activity of osteoclasts, preventing break-down of old bone.
  • the invention stimulates osteoblasts to form new bone.
  • vessel dilator stimulating osteoblasts Stimulating osteoblasts to form new healthy bone is a beneficial advance in the treatment of osteoporosis.
  • CNP C-natriuretic peptide
  • FIG. 2 is a graph showing vessel dilator enhanced the proliferation of human osteoblasts over a concentration of range of 10 nM to 10 pM (p ⁇ 0.01 or less) when evaluated by Mann-Whitley test.
  • the 100 pM and 10 pM concentrations in this graph are in the circulating physiologic range of vessel dilator (Daggubati, et al., 1997 Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators. Cardiovascular Res. 36:246-255).
  • Atrial natriuretic peptide also known as atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), or atriopeptin
  • ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule. It is secreted by heart muscle cells to reduce blood pressure by lowering water, sodium and adipose loads on the circulatory system.
  • C-type natriuretic peptide is a 22 amino acid peptide having a 17-amino acid ring, as described by Brevic (U.S. application Ser. No. 12/677,304, filed Sep. 9, 2008), and is generated from the natriuretic peptide precursor C gene (NPPC; GenBank Accession Number NM — 024409.1).
  • extracellular signal-regulated kinase 1/2 are 44-kDa(ERK1) and 42-kDa (ERK2) serine-threonine protein kinases that regulate cardiac hypertrophy and myocyte survival, cell proliferation, and cell differentiation.
  • MAP kinase kinase 1/2, MEK1/2 mitogen-activated protein kinase kinase 1/2, MEK1/2
  • MAPKs ERK-1/2
  • MEK 1/2 mitogen-activated protein kinase 1/2
  • MEK 1/2 are dual specificity kinases that activate MAPKs having a size of about 45 kDa (MEK 1) and 44 kDa (MEK 2).
  • MEK 1/2 are highly specific, phosphorylating and activating the 44 kDa and 42 kDa MAP kinases, and responsible for promoting cell cycle progression.
  • MEK 1/2 also play an important role in modulating the survival of hematopoietic cells, and the differentiation of certain cell types, such as neuronal cells, maturation of thymocytes from CD4 ⁇ CD8 ⁇ to CD4 + CD8 + cells, and development of the visual cortex.
  • mitogen-activated protein kinase is a serine/threonine-specific protein kinase that responds to extracellular stimuli to regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.
  • patient is used herein to describe an animal, preferably a human, to whom treatment, including prophylactic treatment, with the compounds according to the present invention, is provided.
  • treatment including prophylactic treatment, with the compounds according to the present invention.
  • patient refers to that specific animal.
  • an effective amount is used herein to describe concentrations or amounts of compounds, such as vessel dilator, that are effective for producing an intended result including regulating growth and differentiation of osteoblasts, to address skeletal disorders or other pathologic conditions including achondroplasia skeletal dysplasias and other dysplasias, short stature, osetopenia, osteoporosis, osteomalacia, hypoparathyroidism, tumor associated osteomalacia, rickets, osteogenesis imperfecta, osteitis fibrosa cystic secondary to hyperparathyroidism, Paget's Disease, and osteitis deformans.
  • Compositions according to the present invention may be used to effect proliferation and differentiation of osteoblastic cells to produce a favorable change in the bone or skeletal tissue, or in the disease or condition treated, whether that change is an improvement such as stopping or reversing the degeneration of a disease or condition, reducing a bone density deficit, or a complete cure of the disease or condition treated.
  • administering is used throughout the specification to describe the process by which compounds of the subject invention, such as vessel dilator, are delivered to a patient for therapeutic purposes.
  • Compounds of the subject invention can be administered a number of ways including, but not limited to, parenteral (such term referring to intravenous and intra-arterial as well as other appropriate parenteral routes), subcutaneous, intraperitoneal, intraventricular, among others which term allows compounds of the subject invention to diffuse to the ultimate target site where needed.
  • the compounds can be administered systemically or to a target anatomical site, permitting the compounds to contact target cells, causing the target cells to proliferate and/or differentiate in response to the compounds (e.g., site-specific differentiation).
  • Administration will often depend upon the disease or condition treated and may preferably be via a parenteral route, for example, intravenously, or by direct administration into the affected bone.
  • vessel dilator may be administered via direct injection into the bone, or may be administered systemically.
  • the route of administration for treating an individual is systemic, via intravenous, intra-arterial administration, subcutaneous, or intraperitoneal administration.
  • compositions may further comprise a pharmaceutically acceptable carrier.
  • the compositions used in the present methods can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspension, suppositories, injectable and infusible solutions, and sprays. The preferred form depends on the intended mode of administration and therapeutic application.
  • the compositions also preferably include conventional pharmaceutically acceptable carriers and diluents which are known to those skilled in the art.
  • Examples of carriers or diluents for use with the subject compounds include, but are not limited to, water, saline, ethanol, dimethyl sulfoxide, gelatin, cyclodextrans, magnesium stearate, dextrose, cellulose, sugars, calcium carbonate, glycerol, alumina, starch, and equivalent carriers and diluents, or mixtures of any of these.
  • vessel dilator can be diluted to give a concentration in either 0.9% saline (ie normal saline) or D5W (dextrose 5% in water) for infusion.
  • a cell line (ATCC number CRL-11372) of human osteoblast cells was purchased from the American Type Culture Association (ATCC, Manassas, Va.). Propagation of the human osteoblast cells was in a 1:1 mixture of Ham's F12 Medium and Dulbecco's Modified Eagles Medium (DMEM) with 2.5 mM L-glutamine without phenol red. Base medium was supplemented with 0.3 mg/mL of Geneticin (G418) antibiotic and 10% fetal bovine serum (Harris S A, et al. 1995 Developmental and characterization of a conditionally immortalized human fetal osteoblastic cell line. J Bone Miner Res 10:178-186). Cells were incubated at a temperature of 34° C.
  • DMEM Dulbecco's Modified Eagles Medium
  • the proliferation assay detects the number of viable cells in proliferation using a tetrazolium compound (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt; MTS) and an electron coupling reagent [phenazine ethosulfate (PES)].
  • MTS a tetrazolium compound
  • PES electron coupling reagent
  • PES has enhanced chemical stability, which allows it to be combined with MTS to form a stable solution (Cory A H, et al. 1991 Use of aqueous soluble tetrazolium/formazan assay for growth assays in culture. Cancer Commun 3:207-212).
  • the MTS tetrazolium compound (Owen's reagent) is bioreduced by living cells into a colored formazan product that is measurable at 490 nM in a spectrophotometer, thereby eliminating any nonviable (i.e. dead) cells that would not be proliferating (Cory A H, et al. 1991 Use of aqueous soluble tetrazolium/formazan assay for growth assays in culture. Cancer Commun 3:207-212). This method measure only viable cells' proliferation as dead cells are unable to reduce the MTS tetrazolium compound to a colored formazan product.
  • there was a minus 1% enhancement and at 100 pM, there was a minus 16% enhancement of osteoblast proliferation with CNP, seen in FIG. 1 .
  • Decreasing the concentration of vessel dilator 10-fold to 1 nM resulted in a 6% enhancement of the proliferation of human osteoblasts (p ⁇ 0.01).
  • CNP is expressed in fetal bones and accelerates longitudinal growth of fetal rat metatarsal bones in organ culture (Mericq V, et al. 2000 Regulation of fetal rat bone growth by C-type natriuretic peptide and cGMP. Pediatr Res 47:189-193).
  • CNP in the present investigation was found to stimulate human osteoblast proliferation for the first time, extending previous findings that CNP can enhance osteoblast proliferation in rat (Hagiwara H, et al. 1996 cGMP produced in response to ANP and CNP regulates proliferation and differentiation of osteoblastic cells. Am J Physiol 270:C1311-C1318) and mouse (Suda M, et al.
  • CNP C-type natriuretic peptide
  • NPR-B natriuretic peptide receptor B
  • mice overexpressing CNP in cartilage have skeletal overgrowth (Yasoda A, et al. 2004 Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med 10:80-86), and a 14-y-old girl with overexpression of CNP, with a doubling of CNP in plasma, had bone overgrowth and who was >97 percentile in length at birth and had arachnodactyly of hands and feet with a very long hallux bilaterally at 14 years old (Bocciardi Re al.
  • CNP C-type natriuretic peptide
  • the gene for CNP is expressed in bone (Mericq V, et al. 2000 Regulation of fetal rat bone growth by C-type natriuretic peptide and cGMP. Pediatr Res 47:189-193) to allow it to be an autocrine/paracrine regulator of bone.
  • This is the first investigation demonstrating that vessel dilator, a linear structured peptide hormone as opposed to a ring-structured CNP (Brenner B M, et al. 1990 Diverse biological action of atrial natriuretic peptide. Physiol Rev 70:665-699; Vesely D L 2003 Natriuretic peptides and acute renal failure.
  • cGMP would seem to be an important mediator of their effects because CNP can increase this intracellular mediator in chondrocytes (Hagiwara H, et al. 1994 Autocrine regulation of rat chondrocyte proliferation by natriuretic peptide C and its receptor, natriuretic peptide receptor-B. J Biol Chem 269:10729-10733) and the majority of vessel dilator's effects are mediated via cGMP (Brenner B M, et al. 1990 Diverse biological action of atrial natriuretic peptide.
  • cGMP itself is important for bone development, which have been shown to regulate proliferation and differentiation of osteoblasts and chondrocytes (Hagiwara H, et al. 1996 cGMP produced in response to ANP and CNP regulates proliferation and differentiation of osteoblastic cells.
  • Vessel dilator appears to inhibit MEK 1/2 kinases in proliferating cells through cGMP.
  • contacting cells with a cGMP antibody blocks vessel dilator effects on MEK 1/2 kinases.
  • cGMP itself can inhibit MEK 1/2 kinases in proliferating cells (Sun Y, et al. 2007 Vessel dilator and kaliuretic peptide inhibit MEK 1/2 activation in human prostate cancer cells.
  • Anticancer Res 27:1387-1392 can inhibit MEK 1/2 kinases in proliferating cells.
  • CNP and 8-bromo cGMP also inhibit mitogen-(fibroblast growth factor) stimulated ERK 1/2 kinases' phosphorylation in ATDC5 cells, a mouse chondrogenic cell line (Ozasa A, et al. 2005 Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 36:1056-1064).
  • Vessel dilator inhibits 96% of the phosphorylation of basal activity of ERK 1/2 kinases in proliferating cells (Sun Y, et al. 2006 Vessel dilator and kaliuretic peptide inhibit activation of ERK 1/2 in human prostate cancer cells.
  • CNP has been suggested to be a new treatment strategy for achondroplasia (Ozasa A, et al. 2005 Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. Bone 36:1056-1064). Vessel dilator, with its 36-fold longer half-life and significantly longer biologic effects than CNP, i.e. >12 times longer (Vesely D L, et al. 1994 Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans.
  • Circulation 90:1129-1140 would seem to be a better choice for treatment of bone disease such as dwarfism because it can be given less frequently with similar therapeutic results.
  • vessel dilator stimulates osteoblastic proliferation over a concentration range of 10 nM through 10 pM, whereas CNP at concentration ⁇ 10 nM did not significantly enhance human osteoblast proliferation.
  • CNP's half-life is very short, at about 3 min, in vivo whereas vessel dilator's half-life of >6 h (Vesely D L, et al. 1994
  • Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans.
  • Circulation 90:1129-1140 would suggest it could be given four times per day to affect bone growth.
  • vessel dilator can be given on a reasonable schedule of four times per day, it may have a role in the treatment of short stature in children by enhancing their osteoblast proliferation, indicating that vessel dilator can be utilized in lower concentrations to obtain the same effects as CNP on bone.
  • CNP and vessel dilator may have a therapeutic role in treating a common bone disease in adults, i.e. osteoporosis.
  • Current therapeutic agents for osteoporosis concentrate on inhibiting osteoclasts (Rubin J E, Rubin C T 2009 Biology, physiology, and morphology of bone. In: Firestein G S, et al. (eds) Kelly's Textbook of Rheumatology. 8th ed. Elsevier, Philadelphia, Pa., pp 71-91).
  • Bisphosphonates such as alendronate, parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxy vitamin D, all work via inhibiting osteoclasts (Rubin J E, Rubin C T 2009 Biology, physiology, and morphology of bone.
  • PTH parathyroid hormone
  • calcitonin 1,25-dihydroxy vitamin D
  • Sex steroids such as estrogens and testosterone do stimulate osteoblasts (Rubin J E, Rubin C T 2009 Biology, physiology, and morphology of bone.
  • Sodium fluoride stimulates osteoblasts and has been used for vertebral fractures but even though bone mass increased secondary to sodium fluoride, it does not decrease the incidence of fractures.
  • An agent that stimulates osteoblasts without the side effects of sodium fluoride or sex steroids and that will cause bone formation via osteoblasts rather than inhibiting old bone in place (via osteoclasts) has been sought for decades.
  • vessel dilator was demonstrated to stimulate human osteoblasts, suggesting that it may provide a new therapeutic option for bone disease.
  • Vessel dilator would be a preferred option over CNP because of its much longer biologic activity for >6 h compared with ⁇ 30 min for CNP (Vesely D L, et al.

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EP3659624A1 (fr) 2014-01-15 2020-06-03 The U.S.A. as represented by the Secretary, Department of Health and Human Services Agents de ciblage du cartilage et leur utilisation

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