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WO2002028421A1 - Procedes d'inhibition de la stenose et/ou sclerose de la valvule aortique - Google Patents

Procedes d'inhibition de la stenose et/ou sclerose de la valvule aortique Download PDF

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Publication number
WO2002028421A1
WO2002028421A1 PCT/US2001/031605 US0131605W WO0228421A1 WO 2002028421 A1 WO2002028421 A1 WO 2002028421A1 US 0131605 W US0131605 W US 0131605W WO 0228421 A1 WO0228421 A1 WO 0228421A1
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angiotensin
converting enzyme
aortic valve
ace
aortic
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Kevin D. O'brien
Catherine M. Otto
Jeffrey L. Probstfield
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University of Washington
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University of Washington
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Priority to US10/398,492 priority Critical patent/US20040057955A1/en
Priority to AU2002211581A priority patent/AU2002211581A1/en
Publication of WO2002028421A1 publication Critical patent/WO2002028421A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • the present invention relates to methods of treating calcific aortic valve disease of a mammal by the administration of agents capable of inhibiting the amount and/or activity of angiotensin II in the aortic valve of the mammal.
  • Calcific aortic valvular disease has been recognized as a distinct clinical entity since the early 1900's. Aortic valve changes are seen in 21-25% of adults over age
  • Aortic sclerosis likely represents an early stage in the development of aortic stenosis, and refers to thickening and calcification of the aortic valve leaflets in the absence of obstruction to left ventricular outflow (Otto et al, N.Engl.J.Med.341:142-147; Stewart et al., J.Am.Coll.Cardiol.29:630-634).
  • the valvular pathology has progressed to cause obstruction to left ventricular outflow.
  • Aortic stenosis which has a prevalence of 2-3% in the elderly, is associated with a five-year risk of valve replacement or death of
  • aortic sclerosis and stenosis contain chronic inflammatory cells (Otto et al., Circulation 90:844-853; Olsson et al., J.Am.Coll.Cardiol.24: 1664- 1671; Olsson et al., J.Am.Coll.Cardiol.23: 1162-1170), that a subset of aortic lesion cells actively express osteopontin, a molecule implicated in the regulation of calcification in both normal and pathological states (O'Brien et al., Circulation 92:2163-2168), and that plasma lipoproteins are deposited in aortic lesions (O'Brien et al, Arterioscler.Thromb.Nasc.Biol.16:523-532).
  • angiotensin II type 1 (AT-1) receptors which are the major cellular receptors for angiotensin II, are present in sclerotic through stenotic aortic valve lesions, but are not found in normal valve fibrosa. Accordingly, it has now been discovered that patients with aortic valve disease may be advantageously treated with pharmacological agents that decrease the amount and/or biological activity of angiotensin II in order to prevent the progression and/or complications of aortic valve disease.
  • the present invention provides new methods for treating a patient suffering from calcific aortic valve disease by administering to the patient a therapeutically effective amount of an agent capable of inhibiting the amount and/or activity of angiotensin II in the aortic valve of the patient.
  • the present invention provides methods for decreasing the amount and/or biological activity of angiotensin II in the aortic valve in an animal.
  • a human or non-human animal in need of such treatment is administered an amount of an agent, selected from the group consisting of angiotensin converting enzyme antagonists and angiotensin type 1 receptor antagonists, effective to decrease the amount and/or biological activity of angiotensin II in the aortic valve in the animal.
  • an agent selected from the group consisting of angiotensin converting enzyme antagonists and angiotensin type 1 receptor antagonists, effective to decrease the amount and/or biological activity of angiotensin II in the aortic valve in the animal.
  • the present invention provides methods for decreasing the lipoprotein-mediated deposition of angiotensin converting enzyme in aortic valve lesions in an animal by decreasing the plasma lipoprotein levels in the animal and/or by inhibiting lipoproteins binding to aortic valve lesions, such as by inhibiting expression in the lesions of extracellular matrix molecules to which angiotensin converting enzyme- containing lipoproteins may bind.
  • the methods of the invention are useful in any situation where it is desirable to decrease angiotensin converting enzyme amount and/or biological activity.
  • the methods of the invention can be used to prevent the progression and/or complications associated with aortic valve disease.
  • FIGURE 1 shows a photomicrograph with serial sections of a sclerotic human aortic valve with immunostaining for ACE (FIGURE 1A), ApoB (FIGURE IB), and
  • FIGURE 1C AngE (FIGURE 1C) co-localization.
  • the aortic lumen is located at the top of the image and the left ventricular cavity is located at the bottom of the image.
  • FIGURE 2 shows an immunoblot performed with a monoclonal antibody to ACE on LDL isolated from human plasma. A band of the expected molecular size of angiotensin converting enzyme (ACE) is detected on LDL. The location of molecular weight standards is labeled on the blot.
  • FIGURE 3 shows a photomicrograph with positive immunohistochemical staining for angiotensin II Type 1 (AT-1) receptors on cells in a surgically-excised, stenotic aortic valve. Positive immunohistochemical staining is indicated by a black reaction product.
  • AT-1 angiotensin II Type 1
  • FIGURE 4 graphically illustrates the results of a study using Electron Beam Tomography to quantify aortic valve calcium change in patients treated with statin compared with patients that did not receive statin.
  • the term "pharmacological agent” refers to a substance other than food intended to affect the structure or function of a living body.
  • the term "pharmaceutical compound” refers to a substance used as a medication according to the Food, Drug and Cosmetic Act.
  • ACE antagonist and/or "ACE inhibitor” refer to a molecule, which decreases the amount or biological activity of angiotensin converting enzyme. ACE inhibitors are well known in the art for their activity in inhibiting ACE, thereby blocking conversion of the decapeptide angiotensin I to angiotensin II.
  • AT-1 antagonist refers to a molecule, which decreases the amount or biological activity of angiotensin II type 1 receptor.
  • low density lipoproteins refers to an important class of serum lipoproteins in which a spherical hydrophobic core of triglycerides or cholesterol esters are surrounded by an amphipathic monolayer of phospholipids, cholesterol and/or apolipoproteins (especially apolipoproteins).
  • aortic valve refers to the heart valve that divides the left ventricle and the aorta. The aortic valve opens during left ventricular contraction and then closes to prohibit the backwash of oxygenated blood from the aorta into the ventricle.
  • the aortic valve typically contains has 3 valve leaflets in most individuals, but may contain 2 valve leaflets in some individuals.
  • aortic valve disease refers to a disease state in which there is calcification and fibrosis of the aortic valve, encompassing aortic sclerosis and aortic stenosis.
  • aortic sclerosis refers to the thickening and calcification of the aortic valve leaflets in the absence of obstruction to left ventricular outflow.
  • aortic stenosis refers to a condition of valvular pathology in which left ventricular outflow is obstructed.
  • statin refers to HMG Co A reductase inhibitor.
  • the present invention provides methods of decreasing the amount and/or biological activity of angiotensin II in an aortic valve in an animal.
  • methods are provided for prophylactically and/or therapeutically treating an animal in need of such treatment, comprising administering to the animal an amount of an agent, selected from the group consisting of angiotensin converting enzyme (ACE) antagonists and angiotensin II type 1 receptor (AT-1) antagonists, effective to decrease the amount and/or biological activity of angiotensin II in the aortic valve in an animal.
  • an agent selected from the group consisting of angiotensin converting enzyme (ACE) antagonists and angiotensin II type 1 receptor (AT-1) antagonists
  • the methods described in the present invention are applicable to any animal, including mammals, such as human beings.
  • the methods of this aspect of the invention can be used to decrease the amount and/or biological activity of angiotensin II in an aortic valve in any situation where such angiotensin II inhibition is desirable, including situations in which the animal is exhibiting aortic valve disease in the form of aortic sclerosis or aortic stenosis.
  • aortic sclerosis refers to the thickening and calcification of the aortic valve leaflets in the absence of obstruction to the left ventricular outflow. This stage of the disease is characterized by a chronic inflammation with macrophage infiltrate, deposition of plasma lipoproteins, expression of osteopontin and extracellular mineralization.
  • Aortic stenosis refers to the stage in aortic valvular disease in which the valvular pathology has progressed to cause obstruction to left ventricular outflow.
  • a decrease in disease progression of aortic valvular disease is characterized by at least one of the following changes in a component of valvular disease pathology associated with aortic valve disease that occurs as a result of treatment in accordance with the methods of the invention: a decrease in the presence of an inflammatory cell infiltrate, a decrease in plasma lipoprotein deposition, a decrease in calcification of the leaflet (measured, for example, by imaging techniques); a decrease in the level of ACE, Angll or AT-1 in aortic valvular tissue (measured, for example, by immunohistochemistry); or a decrease in the rate of increase in blood flow velocity across the aortic valve, a decrease in transvalvular pressure gradient or a reduction in the rate of decrease of aortic valve function.
  • Imaging techniques useful in the practice of this aspect of the method of the invention include, but are not limited to: echocardiography, fluoroscopy and electron beam tomography (EBT).
  • EBT is an especially useful imaging technique for detecting and quantifying changes in aortic valve leaflet calcification over time.
  • a decrease in the progression of aortic valvular disease may be characterized, for example, by a decrease in the percentage of patients being treated in accordance with the method of the invention that require valve replacement therapy or surgical intervention due to aortic valve disease.
  • Other measurements useful to measure the progression of aortic valvular disease include functional tests such as pulmonary exercise tests.
  • the amount and/or biological activity of angiotensin II is decreased in an animal by a method comprising administering to the animal an amount of an angiotensin converting enzyme (ACE) antagonist effective to decrease the amount of angiotensin II in the aortic valve in the animal.
  • ACE angiotensin converting enzyme
  • representative ACE antagonists include: pharmaceutical compounds that inhibit the amount and/or biological activity of ACE (ACE inhibitors), ACE antisense nucleic acid molecules (such as antisense mRNA, antisense DNA or antisense oligonucleotides), ACE ribozymes, molecules that inhibit the biological activity of ACE (such as anti-ACE antibodies, or a blocking peptide which interacts with the active site of ACE) and molecules that decrease the amount of ACE carried into the aortic valve by plasma low density lipoproteins (LDLs).
  • ACE inhibitors ACE antisense nucleic acid molecules
  • ACE ribozymes molecules that inhibit the biological activity of ACE (such as anti-ACE antibodies, or a blocking peptide which interacts with the active site of ACE)
  • LDLs plasma low density lipoproteins
  • ACE inhibitors for use in the practice of the invention include, without limitation, 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,
  • Suitable ACE inhibitors to be employed in the practice of the invention are well known in the art, and several are used routinely for treating hypertension.
  • captopril and its analogs are described in U.S. Pat. Nos. 5,238,924 and 4,258,027.
  • Enalapril, enalaprilat, and closely related analogs are described in U.S. Pat. Nos. 4,374,829, 4,472,380, and 4,264,611.
  • Moexipril, quinapril, quinaprilat, and related analogs are described in U.S. Pat. Nos. 4,743,450 and 4,344,949.
  • Ramipril and its analogs are described in U.S. Pat. Nos.
  • ACE inhibitors that are approved for use in humans and are commercially available include, without limitation, ramipril, quinapril, captopril, lisinopril, benazepril, enalapril and fosinopril.
  • Effective amounts of ACE inhibitors for use in the practice of the invention will vary depending on the nature of the inhibitor, but will generally be within the amounts generally employed in the art for administration of the inhibitor for other purposes.
  • the ACE inhibitor may generally be administered at dosages in the range of about 0.05 to about 500 mg/day, more preferably about 0.1 to about 250 mg/day and most preferably about 0.2 to about 100 mg day. Optimum dosage will be readily apparent to those skilled in the art for a particular inhibitor.
  • the ACE inhibitors will generally be administered to a patient for a period of time sufficient to effect a measurable inhibition of the progression of aortic sclerosis and/or stenosis, as described herein.
  • ACE antisense nucleic acid molecules useful as ACE antagonists in the practice of the invention may be constructed in a number of different ways provided they are capable of interfering with the expression ACE.
  • an antisense nucleic acid molecule can be constructed by inverting the coding region (or a portion thereof) of ACE relative to its normal orientation for transcription to allow the transcription of its complement.
  • the antisense nucleic acid molecule is usually substantially identical to at least a portion of the target gene or genes.
  • the nucleic acid need not be perfectly identical to inhibit expression. Generally, higher homology can be used to compensate for the use of a shorter antisense nucleic acid molecule.
  • the minimal percent identity is typically greater than about 65%, but a higher percent identity may exert a more effective repression of expression of the endogenous sequence. Substantially greater percent identity of more than about 80% typically is preferred, though about 95% to absolute identity is typically most preferred.
  • the antisense nucleic acid molecule need not have the same intron or exon pattern as the target gene, and non-coding segments of the target gene may be equally effective in achieving antisense suppression of target gene expression as coding segments.
  • a DNA sequence of at least about 30 or 40 nucleotides may be used as the antisense nucleic acid molecule, although a longer sequence is preferable.
  • a representative example of a useful antagonist of ACE is an antisense ACE nucleic acid molecule which is at least ninety percent identical to the complement of the ACE cDNA consisting of the nucleic acid sequence set forth in SEQ ID NO: 1.
  • the nucleic acid sequence set forth in SEQ ID NO: 1 encodes the ACE protein consisting of the amino acid sequence set forth in SEQ ID NO: 2.
  • the targeting of antisense oligonucleotides to bind ACE mRNA is another mechanism that may be used to reduce the level of ACE protein synthesis.
  • the synthesis of polygalacturonase and the muscarine type 2 acetylcholine receptor are inhibited by antisense oligonucleotides directed to their respective mRNA sequences (U.S. Pat. No. 5,739,119 and U.S. Pat. No. 5,759,829).
  • the ACE antagonist is an anti-ACE antibody.
  • antigen useful for raising antibodies can be prepared in the following manner.
  • a nucleic acid molecule (such as an ACE cDNA molecule) is cloned into a plasmid vector, such as a Bluescript plasmid (available from Stratagene, Inc., La Jolla, California).
  • the recombinant vector is then introduced into an E. coli strain (such as E. coli XLl-Blue, also available from Stratagene, Inc.) and the polypeptide encoded by the nucleic acid molecule is expressed in E. coli and then purified.
  • E. coli strain such as E. coli XLl-Blue, also available from Stratagene, Inc.
  • polypeptides can be prepared using peptide synthesis methods that are well known in the art. The synthetic polypeptides can then be used to prepare antibodies.
  • Antibody production includes not only the stimulation of an immune response by injection into animals, but also analogous processes such as the production of synthetic antibodies, the screening of recombinant immunoglobulin libraries for specific-binding molecules (Orlandi et al., Proc. Natl. Acad. Sci. USA 86:3833, 1989, or Huse et al. Science 256:1275, 1989), or the in vitro stimulation of lymphocyte populations.
  • the invention also extends to non-antibody polypeptides, sometimes referred to as blocking peptides, that have been designed to bind specifically to, and inhibit the active site of ACE.
  • non-antibody polypeptides sometimes referred to as blocking peptides
  • the domain of ACE which binds to the substrate angiotensin I can be targeted with a blocking peptide.
  • Other examples of the design of such peptides, which possess a prescribed ligand specificity, are given in Beste et al. (1999, Proceedings of the National Academy of Science 96:1898-1903).
  • An additional strategy suitable for suppression of target gene activity entails the sense expression of a mutated or partially deleted form of the protein encoded by the target gene according to general criteria for the production of dominant negative mutations (Herskowitz I, Nature 329: 219-222 (1987)).
  • Ribozymes can also be utilized to decrease the amount and/or biological activity of ACE, such as ribozymes, which target ACE mRNA.
  • Ribozymes are catalytic RNA molecules that can cleave nucleic acid molecules having a sequence that is completely or partially homologous to the sequence of the ribozyme.
  • ribozyme transgenes are designed that encode RNA ribozymes that specifically pair with a target RNA and cleave the phosphodiester backbone at a specific location, thereby functionally inactivating the target RNA. In carrying out this cleavage, the ribozyme is not itself altered, and is thus capable of recycling and cleaving other molecules.
  • the inclusion of ribozyme sequences within antisense RNAs confers RNA-cleaving activity upon them, thereby increasing the activity of the antisense constructs.
  • Ribozymes useful in the practice of the invention typically comprise a hybridizing region, of at least about nine nucleotides, which is complementary in nucleotide sequence to at least part of the target ACE mRNA, and a catalytic region which is adapted to cleave the target ACE mRNA (see generally, EPA No. 0 321 201; WO88/04300; Haseloff & Gerlach, Nature 334:585-591 [1988]; Fedor & Uhlenbeck, Proc. Natl. Acad. Sci: USA 87:1668-1672 [1990]; Cech & Bass, Ann. Rev. Biochem. 55:599-629 [1986]).
  • the present invention is based at least in part on the discovery that ACE is found in aortic lesions and is associated with low density lipoproteins such as apolipoprotein B as shown in Fig. 1. Furthermore, it has been found that ACE is associated with LDLs in human plasma as shown in Fig. 2. In accordance with these findings, any pharmaceutically acceptable agent that effectively decreases the amount and/or biological activity of ACE in an aortic valve, including a decrease in ACE that is carried into the aortic valve in association with low density lipoprotein(s) (LDLs), may be used as an ACE antagonist in the context of this aspect of the method of the invention.
  • LDLs low density lipoprotein
  • ACE antagonists useful in the practice of this aspect of the invention may either reduce the level of LDL in plasma, therefore limiting the availability of LDL with which ACE could associate, or the molecule may interfere with the binding and/or retention of ACE- containing LDL particles in an aortic valve lesion.
  • molecules that reduce the level of LDL in plasma include statin, lovastatin, pravastatin, simvastatin, atorvastatin, rozuvastatin, nicotinic acid, bile acid resins such as colestipol and cholestyramine, fibric acid derivatives such as gemfibrozil, bezafibrate and fenofibrate, and cholesterol adsorption inhibitors such as ezetemibe.
  • an ACE antagonist may be a molecule that interferes with association of ACE and LDL particles carried in plasma.
  • molecules useful in this aspect of the invention include, but are not limited to, blocking antibodies and small peptides.
  • the biological activity of angiotensin ⁇ is decreased in an animal by a method comprising the step of introducing into the animal an amount of an angiotensin type 1 receptor (AT-1) antagonist effective to decrease the biological activity of angiotensin II in the aortic valve in the animal.
  • angiotensin type 1 receptor AT-1
  • This aspect of the invention is based on the finding that Angiotensin II type 1 (AT-1) receptors which are the major cellular receptors for angiotensin ⁇ , are present in sclerotic through stenotic aortic valve lesions (as shown in Fig. 3), but are not found in normal valve fibrosa.
  • useful AT-1 antagonists in the practice of this aspect of the invention include: pharmaceutical compounds that inhibit the amount and/or biological activity of AT-1, AT-1 antisense nucleic acid molecules (such as antisense RNA, antisense DNA or antisense oligonucleotides), AT-1 ribozymes, or blocking peptides that interact with the extracellular domain of AT-1.
  • AT-1 antisense nucleic acid molecules such as antisense RNA, antisense DNA or antisense oligonucleotides
  • AT-1 ribozymes or blocking peptides that interact with the extracellular domain of AT-1.
  • Pharmaceutical compounds that are useful in the practice of this aspect of the method of the invention include any compounds that inhibit or block angiotensin type 1 receptors and prevent the progression and/or decrease the risk of clinical events associated with aortic valve disease.
  • angiotensin receptor blocking compounds that are approved for use in humans and are commercially available include: losartan, valsartan, irbesatan, telmesartan and candesartan.
  • AT-1 nucleic acid molecules which are at least ninety percent identical to the complement of the AT-1 cDNA consisting of the nucleic acid sequence set forth in SEQ ID NO: 3.
  • the nucleic acid sequence set forth in SEQ ID NO: 3 encodes the AT-1 protein consisting of the amino acid sequence set forth in SEQ ID NO4.
  • Representative methods of constructing an AT-1 antisense nucleic acid molecule include any methods of constructing antisense nucleic acid molecules described in this patent application.
  • the AT-1 antagonist may be an anti-AT-1 antibody.
  • useful antibodies include any methods of antibody preparation known in the art and/or described in this patent application, including the use of recombinant protein and peptide synthesis.
  • the invention also extends to blocking peptides that have been designed to specifically bind and inhibit the angiotensin type 1 receptor substrate binding domain.
  • useful blocking peptides include peptides that inhibit binding of LDL to the extracellular matrix molecules that are present in aortic lesions.
  • Ribozymes useful in the practice of the invention comprise a hybridizing region of at least nine nucleotides, which is complementary in nucleotide sequence to at least part of the target AT-1 mRNA, and a catalytic region which is adapted to cleave the target AT-1 mRNA.
  • Representative methods of producing an AT-1 ribozyme include any methods of ribozyme preparation described in this patent application.
  • Molecules that decrease the amount and/or biological activity of angiotensin II can be delivered into the body of an animal by any suitable means.
  • said antagonists can be introduced into an animal body by application to a bodily membrane capable of absorbing the composition, for example the nasal, gastrointestinal and rectal membranes.
  • said antagonist molecules may be combined with other suitable ingredients, such as carriers and/or adjuvants.
  • suitable ingredients include ointments, creams, gels or suspensions.
  • ACE and AT-1 antagonist molecules also may be impregnated into transdermal patches, plasters and bandages, preferably in liquid or semi-liquid form.
  • Methods of delivery of ACE and AT-1 antagonist molecules also include the administration by oral, pulmonary, parenteral (e.g., intramuscular, intraperitoneal, intravenous (IN) or subcutaneous injection), inhalation (such as a fine powder formulation), transdermal, nasal, vaginal, rectal, or sublingual routes of administration, and can be formulated in dosage forms appropriate for each route of administration.
  • ACE and AT-1 antagonist molecules that are susceptible to degradation may be introduced in association with another molecule, such as a lipid, to protect the peptide from enzymatic degradation.
  • a lipid such as a lipid
  • PEG polyethylene glycol
  • Antisense ACE or AT-1 nucleic acid molecules can be delivered by any art recognized method of delivering nucleic acid molecules into living cells including transduction, transfection, transformation, direct injection, electroporation, virus- mediated gene delivery, amino acid-mediated gene delivery, biolistic gene delivery, lipofection and heat shock. See, generally, Sambrook et al, supra. Representative, non- viral, methods of gene delivery into cells are disclosed in Huang, L., Hung, M-C, and Wagner, E., Non- Viral Vectors for Gene Therapy, Academic Press, San Diego, California (1999).
  • ACE angiotensin converting enzyme
  • Histological grading of aortic lesion severity Paraffin-embedded specimens were examined for morphologic and cellular features using hematoxylin, eosin and Movat's stains. Aortic valvular lesions were defined morphologically as focal areas of mononuclear inflammatory cell infiltrates and extracellular matrix expansion involving the subendothelial region on the aortic side of the leaflets extending into the fibrosa layer of the valve. Histological grading of lesion severity was designated as follows.
  • Late lesions were characterized by subendothelial thickening on the aortic side of the leaflets in areas of disruption of the basement membrane, displacement of the elastic lamina and accumulation of lipid, protein, extracellular mineralization and cellular infiltrate. Late lesions were characterized by significant leaflet destruction with disruption of normal leaflet architecture, severe calcification and macroscopic thickening of the leaflets.
  • Immunohistochemistry methods were performed using the following , polyclonal antibodies: 1) a sheep polyclonal antibody recognizing angiotensin converting enzyme (ACE) (titer 1:750, overnight, Chemicon International, Inc., Temecula, CA), 2) a rabbit polyclonal antibody recognizing angiotensin II (AngirXtiter 1:50, overnight, Cortex Biochem., San Leandro, CA) and 3) a rabbit polyclonal antibody recognizing human apolipoprotein B (titer 1:1000, 60 minute incubation, kind gift of Dr. Thomas Innerarity, Gladstone Institute, San Francisco, CA). The anti-apoB antiserum was extensively characterized and shown to be monospecific for human apoB (data not shown).
  • ACE angiotensin converting enzyme
  • Specimens were washed with phosphate-buffered saline (PBS), and then incubated for either 60 minutes or overnight with the primary antibody. The specimens were washed again with PBS and a biotin-labeled anti-rabbit or anti-sheep antibody was then applied for 30 minutes. An avidin-biotin-peroxidase conjugate (ABC Elite, Vector Laboratories, Burlingame, CA) was then applied for 30 minutes. Standard peroxidase enzyme substrate, 3,3'-diaminobenzidine (Sigma) with NiCl 2 was added to yield a black reaction product. Cell nuclei were counterstained with methyl green.
  • PBS phosphate-buffered saline
  • An avidin-biotin-peroxidase conjugate (ABC Elite, Vector Laboratories, Burlingame, CA) was then applied for 30 minutes. Standard peroxidase enzyme substrate, 3,3'-diaminobenzidine (Sigma) with Ni
  • results of Immunohistochemical Analysis In each specimen, the three anatomic layers (fibrosa, spongiosa and ventricularis) of the valve leaflets were identified and the specimen was characterized as an early or late lesion as previously described. All of the tissue specimens evaluated contained portions of the aorta and several specimens also contained an adjacent coronary artery. The positive ACE staining within these structures served as an internal positive control for the anti-ACE antibody. The ACE staining was localized to the intima of the aorta in all 26 specimens. Microvessels within the adventia of adjacent coronary arteries and of the aorta also stained positively for ACE.
  • ACE In normal valves, ACE was detected only on endothelial cells (data not shown). However, in aortic valve lesions ranging from sclerotic to severely stenotic, ACE was detected in two distributions. The first distribution was cellular, with ACE staining present in macrophages located within lesions. In contrast, resident macrophages within the spongiosa layer did not contain ACE, suggesting that ACE expression was upregulated in lesion macrophages. The second distribution of ACE was extracellular, with ACE being detected only in regions that also contained apolipoprotein B (see Fig 1). Of the two ACE distributions, the extracellular pattern was much more widespread.
  • ACE enzymatic product of ACE
  • Angll the enzymatic product of ACE
  • regions of the lesions that contained extracellular ACE and ApoB indicating that the extracellular ACE was enzymatically active (see Fig 1).
  • the discovery that ACE is present and enzymatically active in aortic lesions demonstrates the utility of treating patients exhibiting aortic valve sclerosis or stenosis with pharmacological inhibitors of the angiotensin converting enzyme to prevent progression and complications of aortic valve disease.
  • Example 2 This example shows that Angll Type 1 (AT-1) receptors were detected in human aortic valve lesions and were not detected in normal valve fibrosa. Furthermore, the AT- 1 receptors were more prominent in late lesions, suggesting up-regulation of these receptors with increasing disease severity.
  • AT-1 Angll Type 1
  • Immunohistochemistry methods Lrimunohistochemistry was performed with a rabbit polyclonal antibody to the angiotensin II type I receptor (AT-1, titer 1:200, overnight, Santa Cruz Biotechnology, Inc.) on the aortic valve tissues described in Example 1. In addition, an antibody was used against alpha smooth muscle actin (anti- - actin, titer 1:1000 for one hour, Boehringer-Mannheim Biochemica), which is expressed by myofibroblasts. Results of _-mmunohistochemical Analysis: AT-1 receptors were not detected in fibroblasts of normal valve fibrosa (data not shown). However, AT-1 receptors were detected in sclerotic through stenotic aortic valve lesions (see Fig 3).
  • AT-1 receptors were more prominent in late lesions, suggesting up-regulation of these receptors with increasing disease severity.
  • AT-1 receptors when present in aortic valve lesions, were localized to a subset of oc-actin positive fibroblasts (myofibroblasts). These myofibroblasts were present in increased numbers at the leaflet tips of both normal and lesion-containing valves.
  • AT-1 the major cellular receptor for Angll is expressed in aortic lesions demonstrates the utility of treating patients exhibiting aortic valve sclerosis or stenosis with pharmacological inhibitors of the angiotensin II Type 1 receptor to prevent progression and complications of aortic valve disease.
  • Example 3 The discovery that AT-1, the major cellular receptor for Angll is expressed in aortic lesions demonstrates the utility of treating patients exhibiting aortic valve sclerosis or stenosis with pharmacological inhibitors of the angiotensin II Type 1 receptor to prevent progression and complications of aortic valve disease.
  • LDL Low density lipoprotein
  • ACE is present in association with LDL in human plasma as well as in aortic lesions demonstrates the utility of treating patients with aortic valve sclerosis or stenosis with pharmacological agents that decrease the delivery of ACE by , LDL to lesions, either by a) lowering plasma LDL levels or b) interfering with LDL retention on lesion extracellular matrix.
  • the applications of a therapy that decreases the amount of ACE associated with plasma LDL extends beyond aortic valve disease to a variety of disease states including atherosclerosis, renal diseases, pulmonary diseases, hepatic diseases, reproductive diseases and neurological diseases where lipoproteins serve as a vehicle for delivery of ACE to tissues.
  • Clinical Protocol This pilot study enrolled 8 patients with mild to moderate aortic stenosis, normal left ventricular (LV) function and no history of coronary artery disease. At baseline, patients had an echocardiogram, history, measurements of blood pressure and heart rate and a basic chemistry panel. Patients then were placed on the ACE inhibitor ramipril, 2.5 mg qd for 2 weeks followed by up-titration at 2 week intervals to 2.5 mg bid, 5 mg bid and 7.5 mg bid. The study lasted 8 weeks. Vital signs were repeated weekly, chemistry panels every 2 weeks and echocardiograms every 4 weeks.
  • Creatinine (mg/dl), mean ⁇ SD 1.1+0.3
  • Example 5 This example shows that treatment of patients to lower LDL levels through statin therapy correlates over time with lower calcification of the aortic valve which is an indication of a decrease in aortic valve disease progression as measured by Electron Beam Tomography (EBT) scanning.
  • EBT Electron Beam Tomography
  • Study population Retrospective analysis were performed on 620 asymptomatic patients [513 men and 107 women, mean age 59 (range 30-86) years], referred by their primary physicians for Electron Beam Tomography (EBT) scanning to evaluate coronary artery calcium, and who had undergone 2 consecutive EBT scans with an interscan interval of at least 6 months.
  • Exclusion criteria were a history of left ventricular dysfunction or clinical evidence of coronary artery disease, including angina pectoris, previous coronary artery bypass graft surgery or previous percutaneous coronary interventions.
  • Smoking was defined as the use of >10 cigarettes/day.
  • Patients receiving insulin or oral hypoglycemic agents were classified as having diabetes mellitus. Patients were classified as having hypertension if they were receiving anti- hypertensive medications or had known but untreated hypertension. Hyperlipidemia was defined as use of cholesterol lowering medication or, in the absence of cholesterol lowering medication use, as having a total serum cholesterol >240 mg/dL. Patients were classified as receiving statin if they were receiving a statin drug at the time of both the initial and follow-up scans; no patients classified as not receiving statin were receiving statin at the time of either scan.
  • EBT scans were performed using an Imatron C-150XL Ultrafast Computed Tomographic Scanner (Imatron, South San Francisco, Calif.) with an acquisition time of 100 ms/image, ECG triggering at 80% of the RR interval and a slice thickness of 3 mm. A total of 30 consecutive images were obtained during two breath- holding periods from the aortic arch to the apex of the heart. Foci with a density of > 130 Houndsfield units and area > 3 contiguous pixels were regarded as calcification.
  • AVC aortic valve calcium
  • Definite progression of AVC was defined as volumetric or Agatston score change of >18%, which is 2 times the published median interscan variability for the volumetric score (8.9%) by the formula: [(AVC on follow- up EBT Scan - AVC on initial EBT Scan)/(AVC on initial EBT Scan X InterScan Interval in years)] X 100.
  • Definite progression of AVC was defined as volumetric or Agatston score change of >18%, which is 2 times the published median interscan variability for the volumetric score (8.9%) by the formula: [(AVC on follow-up EBT Scan - AVC on initial EBT Scan)/(AVC on initial EBT Scan X InterScan Interval in years)] X 100.
  • AVC progression of AVC was defined as volumetric or Agatston score change of >18%, which is 2 times the published median interscan variability for the volumetric score (8.9%) (Callisster et al, Radiology, 1998).
  • the frequency of definite AVC progression between those receiving statin therapy and those not receiving statin therapy was compared by chi-square test.
  • Clinical characteristics of patients receiving and not receiving statin therapy were compared using t-test for continuous variables and chi- square test for categorical variables. Multivariate analysis was performed to evaluate the relationship between increasing AVC score and cardiovascular risk factors and statin therapy. Significance was defined as p ⁇ 0.05.

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Abstract

L'invention concerne des procédés permettant de diminuer la quantité et/ou l'activité biologique de l'angiotensine II dans la valvule aortique. Les procédés consistent à administrer à l'animal une quantité d'un antagoniste de l'enzyme de conversion de l'angiotensine et/ou un antagoniste du récepteur de type 1 de l'angiotensine II, efficace pour réduire la quantité et/ou l'activité biologique de l'angiotensine II dans la valvule aortique de l'animal.
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