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EP1158997A2 - Methode de stimulation de la proliferation de myocytes et de la reparation des tissus myocardiques - Google Patents

Methode de stimulation de la proliferation de myocytes et de la reparation des tissus myocardiques

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Publication number
EP1158997A2
EP1158997A2 EP00916209A EP00916209A EP1158997A2 EP 1158997 A2 EP1158997 A2 EP 1158997A2 EP 00916209 A EP00916209 A EP 00916209A EP 00916209 A EP00916209 A EP 00916209A EP 1158997 A2 EP1158997 A2 EP 1158997A2
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EP
European Patent Office
Prior art keywords
seq
group
tyr
ala
phe
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP00916209A
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German (de)
English (en)
Inventor
Kathleen Rodgers
Gere Dizerega
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University of Southern California USC
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University of Southern California USC
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Application filed by University of Southern California USC filed Critical University of Southern California USC
Publication of EP1158997A2 publication Critical patent/EP1158997A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0657—Cardiomyocytes; Heart cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/085—Angiotensins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/32—Angiotensins [AT], angiotensinogen

Definitions

  • This present invention relates to myocyte proliferation and differentiation and to myocardial tissue repair.
  • Ventricular myocytes of the adult mammalian myocardium have traditionally been considered to be terminally differentiated cells, incapable of proliferation. (Kardami, Mol. and Cell. Biochem. 92:129-135 (1990)). Soon after birth these cells stop dividing and subsequent muscle growth is brought about by increases in cell size (hypertrophy) rather than cell number. Id. However, evidence indicates that ventricular myocytes have not lost their proliferative potential irreversibly, since they can be induced to synthesize DNA in culture. (Claycomb and Bradshaw, E>ev. Biol. 90:331-337 (1983)). Atrial myocytes of the adult heart retain mitotic potential to a significant extent (Rumyanchev, Int. Rev. Cytol.
  • MI myocardial infarction
  • Infarct size and location are key prognostic factors for outcomes after acute MI.
  • cardiac fibrosis plays a role in the development of congestive heart failure in post-MI heart.
  • fibrosis remote to the MI is considered the major feature of adverse tissue structure.
  • Increased myocardial collagen concentration and abnormal matrix structure adversely alters myocardial stiffness, leading to ventricular diastolic dysfunction.
  • Damaged cardiac muscle is eventually replaced by scar tissue formed by non-muscle cells converging at the site of injury. This compromises cardiac performance further and shortens cardiac lifespan.
  • Reperfusion therapy is an accepted therapy for MI patients, and its application early in MI has been shown to reduce infarct size and increase survival.
  • a number of drug classes administered in this manner have been shown to result in smaller infarct size, including free radical scavengers, calcium antagonists, ⁇ blockers, magnesium, inhibitors of white blood cell function, inhibitors of cellular adhesion selectin molecules, adenosine (Granger, 1997), and fibroblast growth factor (U.S. Patent No. 4,296,100).
  • free radical scavengers calcium antagonists, ⁇ blockers, magnesium, inhibitors of white blood cell function, inhibitors of cellular adhesion selectin molecules, adenosine (Granger, 1997), and fibroblast growth factor (U.S. Patent No. 4,296,100).
  • ACE angiotensin-converting enzyme
  • diuretics U.S. Patent No. 5,679,545.
  • ACE inhibitors While prolonging survival in the setting of heart failure, ACE inhibitors appear to slow the progression towards end-stage heart failure, and substantial numbers of patients on ACE inhibitors have functional class III heart failure.
  • ACE inhibitors consistently appear unable to relieve symptoms in more than 60% of heart failure patients, and they reduce the mortality of heart failure only by approximately 15-20%. Heart transplantation is limited by the availability of donor hearts Id.
  • myocytes cultured in vitro offers promise for the treatment of various cardiac disorders (U.S. Patent No. 5,679,545).
  • myocytes may be implanted into a patient who has suffered a myocardial infarction prior to the onset of fibrosis, therefore potentially avoiding a weakening in the myocardium that may result in aneurysm formation.
  • myocytes may be used in aneurysm repair.
  • myocytes generated in culture may be used in conjunction with artificial materials to produce substrates for reconstructive cardiac surgery.
  • the present invention provides methods, kits, and pharmaceutical compositions for increasing myocyte proliferation and differentiation by contacting the cells with angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists, either alone or in combination with other growth factors and cytokines.
  • the methods of this aspect of the invention may be used to treat heart failure, to provide myocardial cells that may be transplanted or implanted into a patient that suffers from a cardiac disorder, to study the physiology of cardiac muscle, or to identify pharmaceutical agents that may be useful in the treatment of heart disease.
  • the present invention provides methods and kits to promote myocardial tissue repair following myocardial injury, comprising the administration of angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof or All AT type 2 receptor agonists to a patient in need thereof.
  • myocyte includes any myocardial cell, either fetal or adult in origin. Examples of myocytes include, but are not limited to, those described in U.S. Patent Application 5,580, 779; Smith et al., 1991 supra; and Kardami 1990, supra, all references hereby incorporated in their entirety. As defined herein, “proliferation” encompasses both cell self renewal and cellular proliferation with accompanying differentiation.
  • the term “repair following myocardial infarction” refers to a decrease in the fibrosis and scarring that typically follows MI, and to promoting the production of healthy muscle and tissue at necrotic sites.
  • the term “heart failure” refers to the failure of the heart to pump blood with normal efficiency and thus to provide adequate blood flow to other body organs. Heart failure may be due to failure of the right or left or both ventricles. The signs and symptoms of heart failure depend upon which side of the heart is failing. They can include dyspnea, cardiac asthma, pooling of blood in the systemic circulation or in the liver's portal circulation, edema, cyanosis, and hypertrophy of the heart.
  • Heart failure There are many causes of congestive heart failure including but not limited to coronary artery disease leading to heart attacks and heart muscle weakness, primary heart muscle weakness from viral infections or toxins such as prolonged alcohol exposure, heart valve disease causing heart muscle weakness due to too much leaking of blood or heart muscle stiffness from a blocked valve, hypertension, hyperthyroidism, vitamin deficiencies, and drug use.
  • the aim of therapy for heart failure is to improve the pumping function of the heart.
  • active agents refers to the group of compounds comprising angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All) analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists, either alone, combined, or in further combination with other compounds, for treating or preventing restenosis, such as anticoagulants, platelet aggregation inhibitors, smooth muscle cell proliferation inhibitors, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and antilipidemics.
  • angiotensin converting enzyme inhibitors or "ACE inhibitors” includes any compound that inhibits the conversion of the decapeptide angiotensin I to angiotensin II, and include but are not limited to alacepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzazepril, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, converstatin, delapril, delapril-diacid, enalapril, enalaprilat, enalkiren, enapril, epicaptopril, foroxymithine, fosfenopril, fosen
  • angiotensin The biological formation of angiotensin is initiated by the action of renin on the plasma substrate angiotensinogen (Circulation Research 60:786-790 (1987); Clouston et al., Genomics 2:240-248 (1988); Kageyama et al, Biochemistry 23:3603-3609; Ohkubo et al., Proc. Natl. Acad. Sci. 80:2196-2200 (1983)); all references hereby incorporated in their entirety).
  • the substance so formed is a decapeptide called angiotensin I (Al) which is converted to All by the converting enzyme angiotensinase which removes the C-terminal His-Leu residues from Al, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe- His-Leu [SEQ ID NO:37]. All is a known pressor agent and is commercially available.
  • angiotensinogen angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof; All AT 2 type 2 receptor agonists (hereinafter referred to as the "active agents") are effective in accelerating wound healing and the proliferation of certain cell types. See, for example, co-pending U.S. Patent Application Serial Nos.
  • AII(l-7) elicits some, but not the full range of effects elicited by AIL (Pfeilschifter, et al., Eur. J. Pharmacol. 225:57-62 (1992); Jaiswal, et al., Hypertension 19(Supp. II):II-49-II-55 (1992); Edwards and Stack, J. Pharmacol. Exper. Ther. 266:506-510 (1993); Jaiswal, et al., J. Pharmacol. Exper. Ther. 265:664-673 (1991); Jaiswal, et al, Hypertension 17:1115-1120 (1991); Portsi, et a., Br. J. Pharmacol. 111:652-654 (1994)).
  • Angiotensin II is also known as a potent stimulator of angiogenesis (Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and has been shown to activate collateral circulation via preformed blood vessels in rat kidneys (Fernandez et al., Am. J. Physiol. 243:H869-H875 (1982)).
  • angiotensin II and/or All ATI receptor activation in promoting fibrous tissue formation at MI and remote repair sites, and antagonism of the All receptor has been shown in animal models to influence wound healing at MI and remote repair sites.
  • a preferred class of AT2 agonists for use in accordance with the present invention comprises All analogues or active fragments thereof having p-NH-Phe in a position corresponding to a position 6 of AIL
  • various nonpeptidic agents e.g., peptidomimetics
  • having the requisite AT2 agonist activity are further contemplated for use in accordance with the present invention.
  • the active All analogues, fragments of All and analogues thereof of particular interest in accordance with the present invention comprise a sequence consisting of at least three contiguous amino acids of groups R'-R 8 in the sequence of general formula I R ⁇ -R R ⁇ -R ⁇ -R 8 in which R and R together form a group of formula
  • R B is suitably selected from Arg, Lys, Ala, Citron, Orn, Ser(Ac), Sar, D-Arg and D-Lys,
  • R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Lys, Pro, Aib, Acpc and Tyr;
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer, azaTyr, and Ala;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
  • R 6 is His, Arg or 6-NH 2 -Phe;
  • R 7 is Pro or Ala;
  • R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr, excluding sequences including R 4 as a terminal Tyr group.
  • Compounds falling within the category of AT2 agonists useful in the practice of the invention include the AH analogues set forth above subject to the restriction that R 6 is p-NH - Phe.
  • R A and R B are Asp-Arg, Asp-Lys, Glu-Arg and Glu-Lys.
  • Particularly preferred embodiments of this class include the following: AIII or AII(2-8), Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]; AII(3-8), also known as desl-AIII or
  • R 2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg and D-Lys;
  • R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr;
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer, azaTyr, and Ala;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and
  • R 6 is His, Arg or 6-NH 2 -Phe;
  • R 7 is Pro or Ala
  • R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr.
  • a particularly preferred subclass of the compounds of general formula II has the formula
  • R , R and R are as previously defined. Particularly preferred is angiotensin
  • Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2].
  • Other preferred compounds include peptides having the structures Arg-Val-Tyr-Gly-His-Pro-Phe [SEQ ID NO: 17] and Arg-Val-Tyr-Ala-His-Pro-Phe [SEQ ID NO: 18].
  • the fragment AII(4-8) was ineffective in repeated tests; this is believed to be due to the exposed tyrosine on the N-terminus.
  • the active agents comprise a sequence according to the general formula:
  • RI is selected from the group consisting of Val, Pro, He, norLeu, He, Lys,
  • R2 is selected from the group consisting of Phe, Phe(Br), He and Tyr.
  • AH and its analogues adopt either a gamma or a beta turn (Regoli, et al., Pharmacological Reviews 26:69 (1974).
  • neutral side chains in position R , R and R may be involved in maintaining the appropriate distance between active groups in positions R 4 , R 6 and R 8 primarily responsible for binding to receptors and/or intrinsic activity.
  • Hydrophobic side chains in positions R 3 , R 5 and R 8 may also play an important role in the whole conformation of the peptide and/or contribute to the formation of a hypothetical hydrophobic pocket.
  • R 2 may contribute to affinity of the compounds for target receptors and/or play an important role in the conformation of the peptide. For this reason, Arg and Lys are particularly preferred as R .
  • R 2 may be H, Ala, Orn, Citron, Ser(Ac), Sar, D-Arg, or D-Lys.
  • R 3 may be involved in the formation of linear or nonlinear hydrogen bonds with R 5 (in the gamma turn model) or R 6 (in the beta turn model). R would also participate in the first turn in a beta antiparallel structure (which has also been proposed as a possible structure).
  • R 3 may suitably be selected from Lys, Val, Ala, Leu, norLeu, lie, Gly, Pro, Aib, Acpc and Tyr.
  • R 4 is preferably selected from Tyr, Thr, Tyr (PO ) 2 , homoSer, Ser and azaTyr.
  • Tyr is particularly preferred as it may form a hydrogen bond with the receptor site capable of accepting a hydrogen from the phenolic hydroxyl (Regoli, et al. (1974), supra).
  • R 4 can be Ala.
  • an amino acid with a ⁇ aliphatic or alicyclic chain is particularly desirable. Therefore, while Gly is suitable in position R 5 , it is preferred that the amino acid in this position be selected from He, Ala, Leu, norLeu, and Val.
  • R 6 is His, Arg or 6-NH 2 -Phe.
  • the unique properties of the imidazole ring of histidine e.g., ionization at physiological pH, ability to act as proton donor or acceptor, aromatic character) are believed to contribute to its particular utility as R 6 .
  • conformational models suggest that His may participate in hydrogen bond formation (in the beta model) or in the second turn of the antiparallel structure by influencing the orientation of R 7 .
  • R 7 should be Pro or Ala in order to provide the most desirable orientation of R 8 .
  • both a hydrophobic ring and an anionic carboxyl terminal appear to be particularly useful in binding of the analogues of interest to receptors; therefore, Tyr, He, Phe(Br), and especially Phe are preferred for purposes of the present invention.
  • Analogues of particular interest include the following: TABLE 2
  • polypeptides of the instant invention may be synthesized by any conventional method, including, but not limited to, those set forth in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co., Rockford, 111. (1984) and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2, Academic Press, New York, (1973) for solid phase synthesis and E. Schroder and K. Lubke, The Peptides, Vol. 1, Academic Press, New York, (1965) for solution synthesis.
  • the disclosures of the foregoing treatises are incorporated by reference herein.
  • these methods involve the sequential addition of protected amino acids to a growing peptide chain (U.S. Patent No. 5,693,616, herein incorporated by reference in its entirety). Normally, either the amino or carboxyl group of the first amino acid and any reactive side chain group are protected. This protected amino acid is then either attached to an inert solid support, or utilized in solution, and the next amino acid in the sequence, also suitably protected, is added under conditions amenable to formation of the amide linkage. After all the desired amino acids have been linked in the proper sequence, protecting groups and any solid support are removed to afford the crude polypeptide. The polypeptide is desalted and purified, preferably chromatographically, to yield the final product.
  • peptides are synthesized according to standard solid-phase methodologies, such as may be performed on an Applied Biosystems Model 430A peptide synthesizer (Applied Biosystems, Foster City, Calif), according to manufacturer's instructions. Other methods of synthesizing peptides or peptidomimetics, either by solid phase methodologies or in liquid phase, are well known to those skilled in the art.
  • the peptides can be produced by standard molecular biological techniques.
  • methods, kits, and pharmaceutical compositions for increasing in vivo, in vitro and ex vivo myocyte proliferation by exposure to angiotensinogen, Al, Al analogues, Al fragments and analogues thereof, AH analogues, AH fragments or analogues thereof or AH AT 2 type 2 receptor agonists (hereinafter referred to as the "active agents") is disclosed.
  • active agents AH AT 2 type 2 receptor agonists
  • Proliferation can be quantitated using any one of a variety of techniques well known in the art, including, but not limited to, bromodeoxyuridine incorporation (Vicario-Abejon et al., 1995); Lazarous et al. Biotechnol. and Histochem. 67:253-255 (1992)), 3 H-thymidine incorporation (Fredericksen et al., 1988), or antibody labeling of a protein present in higher concentration in proliferating cells than in non-proliferating cells.
  • proliferation of myocytes is assessed by reactivity to an antibody directed against a protein known to be present in higher concentrations in proliferating cells than in non-proliferating cells, including but not limited to proliferating cell nuclear antigen (PCNA, or cyclin; Zymed Laboratories, South San Francisco, California).
  • PCNA proliferating cell nuclear antigen
  • myocytes are isolated from atrial tissue according to standard methods (Smith et al., 1991, supra), suspended in culture medium, and incubated in the presence of, preferably, between about 0.1 ng/ml and about 10 mg/ml of the active agents of the invention.
  • the cells are expanded for a period of between 8 and 21 days and cellular proliferation is assessed as described above.
  • myocytes are isolated from atrial tissue obtained from cardiovascular surgery patients undergoing procedures requiring "heart-lung bypass.” Smith et al., In Vitro Cell Dev. Biol. 27A:914-920 (1991). The samples are placed in an ice-saline slush immediately after removal, rinsed in saline, and the epicardial covering is removed with a scalpel to reduce the amount of connective tissue included in the cell harvest. The remaining "pure” atrial muscle is minced into 0.5 to 1.0 mm 3 pieces and placed in cold Hanks' balanced salt solution (HBSS) without calcium or magnesium (Whitaker; Walkerville, MD).
  • HBSS cold Hanks' balanced salt solution
  • Myocytes exposed to the active agents as described above can be used, for example, for implantation or transplantation into a patient in need of such treatment.
  • autologous or heterologous cells may be implanted or transplanted into a patient who suffers from a cardiac disorder.
  • cells may be implanted into a patient who has suffered a myocardial infarction prior to the onset of fibrosis, therefore potentially avoiding a weakening in the myocardium that may result in aneurysm formation (U.S. Patent No. 5,580,779).
  • such cells or artificially produced myocardial tissue may be used in aneurysm repair.
  • cells generated in culture may be used in conjunction with artificial materials to produce substrates for reconstructive cardiac surgery.
  • atrial myocardial cells caused to proliferate by the methods of the invention may be used in vivo or in vitro as a source of atrial natriuretic peptide.
  • a cellular implant comprising such cells may be introduced into a patient as a source of atrial natriuretic peptide that is subject to biofeedback mechanism.
  • the cells are cultured in vitro or ex vivo as described above.
  • the cells are rinsed to remove all traces of culture fluid, resuspended in an appropriate medium and then pelleted and rinsed several times. After the final rinse, the cells are resuspended at between 0.7 x 10 6 and 50 x 10 6 cells per ml in an appropriate medium and used as described.
  • a suitable injected dose of active agent is preferably between about 0.1 ng/kg and about 10 mg/kg administered twice daily.
  • the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1 % to 1% of the formulation.
  • the present invention provides methods, pharmaceutical compositions, and kits to promote myocardial tissue repair after myocardial infarction, comprising administration of the active agents of the invention to a patient in need thereof to promote myocardial tissue repair after MI.
  • an area of myocardial tissue is treated in vivo following, or at the time of, myocardial infarction (MI) to promote repair and lessened fibrosis.
  • MI myocardial infarction
  • An effective dose of the active agents is applied to the myocardial tissue, preferably immediately following MI, although it can also be applied when there is an indication of impending MI.
  • a catheter is placed into the coronary artery of a subject between about at the time of to about 24 hours after myocardial infarction and injecting an effective amount of the active agent into the heart of the subject.
  • the concentration of active agent injected is between about 100 ng/kg body weight and about 10.0 mg/kg body weight, as described above.
  • the injection can be repeated as needed to promote myocardial tissue repair following MI. Injections can also be by other routes, including but not limited to by catheter via arterial angiography, intracoronary injection, or in a cardioplegic solution by the aortic route.
  • the active agents may be administered by any suitable route, including parentally, topically, or by cardiovascular devices in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes, subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intracardiac, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally.
  • the active agents can be administered by gene therapy techniques.
  • the active agents of the invention may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions).
  • the compounds of the invention may be applied in a variety of solutions. Suitable solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the peptide, and are not harmful for the proposed application. In this regard, the compounds of the present invention are very stable but are hydrolyzed by strong acids and bases. The compounds of the present invention are soluble in organic solvents and in aqueous solutions at pH 5-8.
  • the active agents may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as carriers, preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
  • conventional adjuvants such as carriers, preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
  • the active agents of the invention can be used alone or in a combination of active agents, or may be used in combination with other agents that promote myocardial tissue repair, including, but not limited to free radical scavengers, calcium antagonists, ⁇ -blockers, magnesium, inhibitors of white blood cell function, inhibitors of cellular adhesion selectin molecules, adenosine, fibroblast growth factor, digoxin, and ACE inhibitors.
  • the active agents can be used in combination with other compounds that promote myocyte proliferation, differentiation, such as growth factors and cytokines including but not limited to epidermal growth factor, insulin-like growth factor, fibroblast growth factor, platelet derived growth factor, nerve growth factor, tumor necrosis factor, and interleukin I.
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the active agents are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • the dosage regimen for the therapeutic methods of the invention is based on a variety of factors, including the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely by a physician using standard methods. Dosage levels of the order of between 0.1 ng/kg and 10 mg/kg body weight active agent per body weight are useful for all methods of use disclosed herein.
  • the treatment regime will also vary depending on the condition of the subject, based on a variety of factors, including the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed.
  • an active agents is administered to a patient as soon as possible after, or at the time of, myocardial infarction and continuing for up to 30 days.
  • the therapy is administered for 1 to 6 times per day at dosages as described above.
  • the active agent is administered via local delivery using cardiovascular devices. Local delivery of the active agents of the invention can be by a variety of techniques that administer the agent at or near the traumatized vascular site.
  • Examples of site-specific or targeted local delivery techniques are not intended to be limiting but to be illustrative of the techniques available. Examples include local delivery catheters, such as an infusion catheter, an indwelling catheter, or a needle catheter, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct applications. (U.S. Patent 5,981,568, incorporated by reference herein in its entirety.)
  • Local delivery by an implant describes the surgical placement of a matrix that contains the active agent into the lesion or traumatized area.
  • the implanted matrix can release the active agent by diffusion, chemical reaction, or solvent activators. See, for example, Lange, Science, 249, 1527 (1990).
  • a stent which is designed to mechanically prevent the collapse and re-occlusion of the coronary arteries or other vessels. Incorporation of an active agent into the stent permits delivery of the active agent directly to the lesion. Local delivery of agents by this technique is described in Koh, Pharmaceutical Technology (October, 1990).
  • a metallic, plastic or biodegradable intravascular stent is employed which comprises the active agent.
  • the stent may comprise a biodegradable coating, a porous or a permeable non-biodegradable coating, or a biodegradable or non-biodegradable membrane or synthetic graft sheath-like coating, e.g., PTFE, comprising the active agent.
  • a biodegradable stent may also have the active agent impregnated therein, i.e., in the stent matrix.
  • a biodegradable stent with the active agent impregnated therein can be further coated with a biodegradable coating or with a porous non-biodegradable coating having a sustained release-dosage form of the active agent dispersed therein.
  • This stent can provide a differential release rate of the active agent, i.e., there can be an initial faster release rate of the active agent from the coating, followed by delayed release of the active agent impregnated in the stent matrix, upon degradation of the stent matrix.
  • the intravascular stent also provides a mechanical means of providing an increase in luminal area of a vessel.
  • the wrap comprises a pharmaceutically acceptable carrier matrix, including but not limited to a Pluronic gel which is free, or contained by a collagen mesh, which gel has dispersed therein the active agent.
  • Another embodiment of the invention is the incorporation of the active agent into the expanded nodal spaces of a PTFE (Impra, Inc., Tempe, Ariz.) vascular graft-like membrane which can surround, or be placed on the interior or on the exterior surface of, an interlumenal vascular stent, which comprises metal or a biodegradable or nonbiodegradable polymer.
  • the active agent, or a sustained release dosage form of the active agent fills the nodal spaces of the PTFE membrane wall and/or coats the inner and/or outer surfaces of the membrane.
  • a suitable local delivery dose of active ingredient of active agent is preferably between about 0.1 ng/kg and about 10 mg/kg administered twice daily for a time sufficient to promote myocardial tissue repair following MI.
  • the concentration of active agent is between about 100 ng/kg body weight and about 10.0 mg/kg body weight.
  • the concentration of active agent is between about 10 ⁇ g/kg body weight and about 10.0 mg/kg body weight.
  • the active agent is administered parentally.
  • Suitable topical doses and active ingredient concentration in the formulation are as described for local delivery via cardiovascular devices.
  • the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO:l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:l l, SEQ ID NO:12, SEQ ID NO:13, SEQ TD NO:16, SEQ ID NO:17, SEQ TD NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ED NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ro NO:31, SEQ ID NO: 32, SEQ ID NO:33, SEQ ID NO:31, SEQ ID NO: 32, SEQ ID NO
  • kits for promoting in vivo myocyte proliferation and differentiation, or myocardial tissue repair following MI wherein the kits comprise an effective amount of active agent for promoting in vivo myocyte proliferation or myocardial tissue repair following MI, and instructions for using the amount effective of active agent as a therapeutic.
  • the kit further comprises a pharmaceutically acceptable carrier, such as those adjuvants described above.
  • the kit further comprises a means for delivery of the active agent to a patient.
  • Such devices include, but are not limited to infusion catheters, indwelling catheters, needle catheters, synthetic grafts, adventitial wraps, shunts, stents or other implantable devices, syringes, matrical or micellar solutions, bandages, wound dressings, aerosol sprays, lipid foams, transdermal patches, topical administrative agents, polyethylene glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (e.g., saline, Ringer's lactate solution, phosphate-buffered saline, etc.), viscoelastics, polyethylene glycols, and polypropylene glycols.
  • the means for delivery may either contain the effective amount of active agent, or may be separate from the compounds, which are then applied to the means for delivery at the time of use.
  • kits further comprise an amount effective to promote in vivo myocyte proliferation and differentiation, or repair of myocardial tissue of at least one compound selected from the group consisting of free radical scavengers, calcium antagonists, ⁇ -blockers, magnesium, inhibitors of white blood cell function, inhibitors of cellular adhesion selectin molecules, adenosine, fibroblast growth factor, other growth factors, cytokines, digoxin, and ACE inhibitors.
  • an improved cell culture medium for the proliferation and differentiation of myocytes, wherein the improvement comprises addition to the cell culture medium of an effective amount of the active agents, as described above.
  • Any cell culture media that can support the growth of myocytes can be used with the present invention.
  • Such cell culture media include, but are not limited to Basal Media Eagle, Dulbecco's Modified Eagle Medium, Iscove's Modified Dulbecco's Medium, McCoy's Medium, Minimum Essential Medium, F-10 Nutrient Mixtures, Opti-MEM® Reduced-Serum Medium, RPMI Medium, and Macrophage-SFM Medium or combinations thereof.
  • the improved cell culture medium can be supplied in either a concentrated (ie: 10X) or non-concentrated form, and may be supplied as either a liquid, a powder, or a lyophilizate.
  • the cell culture may be either chemically defined, or may contain a serum supplement.
  • Culture media is commercially available from many sources, such as GIBCO BRL (Gaithersburg, MD) and Sigma (St. Louis, MO)
  • kits for the propagation of myocytes wherein the kits comprise an effective amount of the active agents, as described above, and instructions for using the active agents to promote myocyte proliferation and differentiation.
  • the kit further comprises cell culture growth medium.
  • Any cell culture media that can support the growth and differentiation of myocytes can be used with the present invention. Examples of such cell culture media are described above.
  • the improved cell culture medium can be supplied in either a concentrated (ie: 10X) or non-concentrated form, and may be supplied as either a liquid, a powder, or a lyophilizate.
  • the cell culture may be either chemically defined, or may contain a serum supplement.
  • the kit further comprises a sterile container.
  • the sterile container can comprise either a sealed container, such as a cell culture flask, a roller bottle, or a centrifuge tube, or a non-sealed container, such as a cell culture plate or microtiter plate (Nunc; Naperville, IL).
  • the kit further comprises an antibiotic supplement for inclusion in the reconstituted cell growth medium.
  • antibiotic supplements include, but are not limited to actimonycin D, Fungizone®, kanamycin, neomycin, nystatin, penicillin, streptomycin, or combinations thereof (GIBCO).
  • the present invention by providing a method for enhanced proliferation of myocytes, will greatly increase the clinical benefits of myocyte cell therapy after various ischemic events, including but not limited to myocardial infarction. This is true both for increased “self-renewal" of myocytes, which will provide a larger supply of myocytes at the appropriate site.
  • methods that increase in vivo proliferation of myocytes are beneficial in treating various ischemic events, including but not limited to myocardial infarction, aneurysm repair, and reconstructive cardiac surgery.
  • the method of the present invention also increases the potential utility of myocytes as vehicles for gene therapy in various ischemic events, including but not limited to myocardial infarction by more efficiently providing a large number of such cells for transfection, and also by providing a more efficient means to rapidly expand transfected myocytes.
  • Administration of the active agents to accelerate in vivo myocyte proliferation and/or to treat myocardial injuries can be used to treat heart failure, cardiomyopathies, inflammation, infection, sepsis, ischemia, heart valve disease, myocarditis, inflammation; or myocardial ischemia and infarction; and for improvement of cardiac output by increasing stroke volume. Examples
  • the dissociated cells were mixed with Eagle's minimal essential medium (MEM; Gibco, MD) containing 10% newborn calf serum, and were centrifuged and pooled.
  • MEM Eagle's minimal essential medium
  • the dissociated cells were enriched for cardiomyocytes by the technique of differential adhesion to tissue culture plastics for 90 minutes at 37°C in a humidified 5% CO and air atmosphere, and plated onto laminin-coated (20 ⁇ g/ml) silicone dishes at a concentration of approximately 4 x 10 5 cells/dish. Cultures were incubated in a humidified 5% CO 2 , 95% air atmosphere at 37°C.
  • the attached cells were rinsed in serum-free medium.
  • standard MEM was supplemented with MEM amino acids, vitamins, penicillin- streptomycin (GIBCO), and 2 mM glutamine.
  • the medium contained 30 nM NaSeO 4 , 2.5 ⁇ g/ml human insulin, 10 ⁇ g/ml human transferrin (Sigma), 0.25 mM ascorbic acid (Sigma) and 0.1 mM 5 -bromo-2' -deoxyuridine to minimize the proliferation of non- myogenic cells.
  • the medium was replaced every 2 days with fresh medium over the course of the experiments.
  • Vehicle (10% Hydron, 60% ethanol, and 1% polyethylene glycol), with and without peptide (1 mg/ml, 0.05 ml) was injected in the cardiac muscle distal to the site of coronary occlusion. The sternum was then closed with 2-0 silk. The muscle and skin were then closed with 3-0 Dexon II suture. Twenty-eight days after surgery, the animals were euthanized and a necropsy was performed. The number of microscopic fields with fibrosis (scar) and the number of blood vessels/field present in the infarct site were assessed by microscopic evaluation. The presence of a blood vessel was defined as a channel lined with endothelial cells that contained red blood cells (indicating that the vessels had a blood source).
  • AH SEQ ID NO:l
  • AII(l-7) SEQ ID NO:4
  • 2 GD SEQ ID NO:39
  • 9GD SEQ ID NO:41

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Abstract

La présente invention concerne des méthodes, des compositions pharmaceutiques, des milieux de culture cellulaire améliorés et des trousses permettant de stimuler la prolifération de myocytes et la réparation des tissus myocardiques suite à une blessure myocardique par contact avec un angiotensinogène, une angiotensine I (AI), des analogues d'AI, des fragments d'AI et leurs analogues, une angiotensine II (AII), des analogues d'AII, des fragments d'AII et leurs analogues et/ou des agonistes de récepteur de type 2 d'AII AT2.
EP00916209A 1999-03-09 2000-03-09 Methode de stimulation de la proliferation de myocytes et de la reparation des tissus myocardiques Withdrawn EP1158997A2 (fr)

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