US20110092430A1 - Method and compound for the treatment of valvular disease - Google Patents
Method and compound for the treatment of valvular disease Download PDFInfo
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- US20110092430A1 US20110092430A1 US12/956,615 US95661510A US2011092430A1 US 20110092430 A1 US20110092430 A1 US 20110092430A1 US 95661510 A US95661510 A US 95661510A US 2011092430 A1 US2011092430 A1 US 2011092430A1
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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
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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
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
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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
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/688—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols both hydroxy compounds having nitrogen atoms, e.g. sphingomyelins
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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
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- 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
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to the general field of medical methods and compounds and is particularly concerned with a method and compound for the treatment of valvular disease.
- the function of the heart is to supply the energy required for the circulation of blood in the cardiovascular system. Blood flow through all organs is passive and occurs only because arterial pressure is kept higher than venous pressure by the pumping action of the heart.
- the right heart pump provides the energy necessary to move blood through the pulmonary vessels and the left heart pump provides the energy that causes flow through the systemic organs.
- the left ventricle of the heart pumps oxygen-rich blood to arteries in the vasculature of the body through the aorta.
- the aortic valve which is located between the left ventricle and the aorta, opens and closes to control the direction of blood flow. More specifically, during heartbeat or systole, the aortic valve is opened to allow blood to flow from the left ventricle into the aorta. Between heartbeats, or during diastole, however, the aortic valve closes to form a tight seal that prevents blood from leaking back into the ventricle.
- the valves are structurally designed to allow flow in only one direction and passively open and close in response to the direction of the pressure differences across them.
- the aortic valve is composed of three fibrous leaflets or cusps. The leaflets are forced open against the walls of the aorta during ventricular ejection of blood but fall back during diastole, their free edges coapting to prevent blood from returning into the heart.
- each aortic valve cusp bulges outward, forming three structures known as sinuses of Valsalva.
- the two most anterior valvular aortic cusps are known as the left and right coronary cusps because of the origin of the left and right coronary arteries from the respective sinuses of Valsalva and the remaining valvular posterior cusp is known as the noncoronary cusp.
- aortic valve stenosis it can happen that the aortic valve is somehow damaged and may become stenosed. When this happens, the aortic valve does not open to its normal extent and the flow of blood from the heart into the aorta is hindered. This leads to a heart condition that is commonly known as aortic valve stenosis.
- aortic valve stenosis Common etiologies for aortic valve stenosis include congenital abnormality, rheumatic fever or degeneration with calcification in the aging patient.
- a bicuspid valve is the most common congenital abnormality, and often a raphe in one of the cusps indicates failure of the commissure to develop. Rarely, a unicuspid or quadricuspid valve can be present at birth. Although the bicuspid valve may not be initially stenotic, fibrosis and thickening lead eventually to reduced orifice size with calcification. Indeed, mechanical sheer stress typically leads to calcific injury.
- Rheumatic fever scars the leaflet margins, and eventually the commissures fuse and calcify. More than 50% of adults with aortic stenosis are found to have a bicuspid valve, but fibrosis and calcification may make it difficult to determine whether the valve is bicuspid or tricuspid.
- aortic stenosis produces an increase in systolic left ventricular pressure.
- Systolic hypertension in the ventricular chamber is compensated by concentric hypertrophy of the myocardial wall, allowing the wall stress to remain normal.
- the less compliant, thickened left ventricle becomes more dependent on the atrial contribution to diastolic filling, such that left ventricular performance can deteriorate when atrial contraction is lost, for example during atrial fibrillation or atrial-ventricular dissociation.
- the abnormal relaxation and increased stiffness of the thickened left ventricle during diastole also result in diastolic dysfunction and elevations of left ventricular and left atrial diastolic pressures.
- Myocardial failure can eventually develop from chronic severe valvular obstruction and depression of the contractile state. Left ventricular dilatation can also occur in some patients. Myocardial oxygen consumption remains high owing to elevation of systolic pressure in the left ventricle and increase in left ventricular mass. In addition, the increased left ventricular diastolic pressure reduces the pressure gradient necessary for myocardial perfusion. Thus, significant aortic stenosis creates conditions in which high myocardial oxygen demands are inadequately supported by reduced oxygen supply, which leads to subendocardial ischemia.
- the ejection fraction is decreased to below the normal range (with or without associated dilatation of the left ventricle). Further elevation of the left ventricular end diastolic pressure (secondary to diastolic dysfunction with or without systolic dysfunction) results in pulmonary venous hypertension.
- the increased myocardial oxygen demands in aortic stenosis with the underperfused subendocardial myocardium can produce angina pectoris, arrhythmias, and even sudden death.
- Calcific aortic stenosis accounts for a large percentage of aortic stenosis cases.
- the condition is characterized by the build-up of calcified nodules on the upper or superior surface of the aortic valve leaflets. These nodules decrease the flexibility of the leaflets, thereby limiting their mobility and capacity to fully open.
- Valve replacement during open-heart surgery, is currently the standard therapy for symptomatic aortic stenosis. Ten-year survival rates for isolated aortic valve replacement are relatively good, even in elderly patients. However, this technique requires the patient to be healthy enough to undergo sternotomy (chest opening) and open heart surgery. The operative mortality for this procedure, particularly in the elderly, is relatively large.
- prosthetic heart valves There are two types of prosthetic heart valves, namely mechanical valves that are composed of only materials that are not derived from living organisms and bio-prosthetic valves that are composed in whole or in part of biological material.
- Mechanical valves currently in use have a ball-cage construction, a tilted disc construction (1 or 2 discs) or a hinged leaflet construction.
- Bio-prosthetic valves generally comprise a supporting stent and a plurality of leaflets.
- the leaflets are generally composed of biological material, while the stent, when present, generally comprises non-biological material, at least in part.
- the biological material of the leaflets can be autologous tissues such as pericardium, fascia lata or cardiac valves. Alternatively, this material can be derived from homologous tissue such as non-autologous human tissue for human implantation or can be xenogeneic.
- Each type of prosthetic heart valve has advantages and disadvantages.
- Mechanical heart valves are durable and, hence, more likely to result in long-lasting function but require careful chronic anticoagulation because of thrombo-embolic risk.
- Chronic anticoagulation therapy carries with it a risk of haemorrhage similar in incidence to that of the residual risk for thrombotic events.
- Bio-prosthetic valves initially approximate the haemodynamic properties of the natural valve. They carry a smaller risk of complications secondary to thrombus than do mechanical valves. Such valves, however, carry a significantly higher risk of calcification than mechanical valves. Since treatment of a functionally compromised bio-prosthetic heart valve frequently requires replacement with a new valve (and hence a second open-heart surgery), limitations on the useful life expectancy of a bio-prosthetic heart valve are both a serious medical problem for the patient and a financial drain on the medical system.
- prosthetic heart valves are somewhat stenotic.
- Prosthetic dysfunction secondary to thrombosis or calcification can lead to increased obstruction or the development of regurgitation.
- Regurgitation can also result from a perivalvular leak, that is a leak in the area of the sewing ring of the valve.
- Turbulence associated with valve dysfunction can cause haemolysis and anemia. Even normally functioning prosthetic valves can cause haemolysis in some patients.
- Endocarditis is another potential and major complication in patients with prosthetic heart valves.
- Antibiotic prophylaxis has to be administered prior to dental, gastro-intestinal and genito-urinary surgery and other procedures associated with bacteraemia.
- Intra-operative mechanical debridement or decalcification of the aortic valve was used for many years prior to the advent of mechanical replacement valves.
- the aorta is entered surgically but, rather than replace the valve manually, the surgeon removes the calcified deposits, using suitable surgical tools.
- ultrasonic debridement has also been demonstrated to be effective to remove calcific deposits. Nevertheless, this technique still requires the patient to be healthy enough to survive and recuperate from thoracic surgery, and involves all the costs and risks attendant with such surgery.
- a third technique for correcting aortic stenosis involves percutaneous balloon aortic valvuloplasty.
- an inflatable balloon catheter is advanced to the aortic valve and inflated to compress and fracture the calcified nodules in an attempt to increase leaflet mobility.
- the present invention differs significantly from the prior art and current trends by providing a method for not only preventing the progression of aortic stenosis but also for reducing the degree of stenosis using a reverse lipid transport agonist.
- An object of the present invention is therefore to provide a novel non-surgical treatment of valvular disease.
- the invention provides a method for preventing or treating a valvular stenosis in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist.
- a reverse lipid transport agonist is a reverse cholesterol transport agonist.
- the valvular stenosis is an aortic valve stenosis, a calcific valve stenosis, or any other valvular stenosis.
- the reverse lipid transport agonist is selected from the group consisting of: an HDL, a peptide with HDL-like physiological effects, a peptide with HDL-like physiological effects complexed to a lipid, an HDL-mimetic agents, a CETP modulator, an SRB1 modulators, an LXR/RXR agonist, an ABCA1 agonists, a PPAR agonist and an Apolipoprotein A-I (ApoA-1) mimetic peptide/phospholipid complex.
- administering the ApoA-1 mimetic peptide/phospholipid complex may include injecting the ApoA-1′ mimetic peptide/phospholipid complex in the subject.
- dosages in this case are of from about 1 ⁇ g to about 10 g per kg body weight of the subject, about 1 mg to about 0.5 g per kg body weight of the subject, and about 25 mg per kg body weight of the subject.
- the ApoA-1 mimetic peptide has the sequence of SEQ ID NO: 1 found herein below, and the ApoA-1 mimetic peptide may be complexed with egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).
- DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
- the subject is a mammal, for example a human.
- the invention provides a method for preventing or treating a valvular calcification in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist.
- the invention provides a method for controlling a valvular stenosis in a subject, the method comprising increasing reverse cholesterol transport in a subject in need thereof.
- the invention provides a method for preventing or reversing valvular stenosis, the method comprising administering to a patient in need thereof a reverse lipid transport agonist.
- the invention provides a method for controlling a valvular stenosis in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist.
- controlling the valvular stenosis may include reducing a rate of progression of the valvular stenosis, or reversing, at least in part, the valvular stenosis.
- the invention provides the use of a reverse lipid transport agonist for controlling valvular stenosis in a subject.
- the invention provides the use of a reverse lipid transport agonist for the manufacture of a pharmaceutical composition of matter for controlling valvular stenosis in a subject
- the method comprises the administration of a therapeutically effective amount of a compound, referred to hereinafter as compound A, that mimics biologic properties of Apolipoprotein A-1 (ApoA-1).
- compound A a compound that mimics biologic properties of Apolipoprotein A-1 (ApoA-1).
- compound A a compound that mimics biologic properties of Apolipoprotein A-1
- Compound A and other suitable compounds are described in U.S. Pat. Nos. 6,287,590, issued Sep. 11, 2001, and 6,506,799, issued Jan. 14, 2003, which are hereby incorporated by reference in their entirety. Indeed, it is believed that in view of current knowledge regarding the action of the compounds and molecules described in these patents, results similar to those presented herein are obtainable with these compounds and molecules.
- the proposed method replaces relatively invasive or relatively ineffective existing treatments for valvular diseases. Also, in addition to slowing the progression of valvular disease, the proposed method also reverses valvular stenosis. Accordingly, the proposed treatment not only has a potential to slow down or stop the progression of aortic valve stenosis and other valvular diseases, but also to cause the regression of aortic valve stenosis and other valvular diseases.
- Aortic valve stenosis is the most common valvular heart disease, and standard curative therapy remains open-heart surgical valve replacement.
- AVS Aortic valve stenosis
- ApoA-1 mimetic peptide infusions were tested to determine if they could induce regression of AVS.
- Aortic valve thickness decreased by 21% within 14 days of treatment in the treated group (0.094 ⁇ 0.034 cm vs. 0.075 ⁇ 0.033 cm) whereas it was unchanged in controls (P 0.0006).
- FIG. 1 illustrates aortic valve area values obtained through echocardiographic measurements obtained during the ApoA-1 mimetic peptide treatment period.
- Day “0” corresponds to the end of cholesterol plus vitamin D 2 diet and the beginning of ApoA-1 mimetic peptide treatment period, *P ⁇ 0.05; **P ⁇ 0.01.
- (b) Aortic valve thickness values, ***P ⁇ 0.001;
- FIG. 2 illustrates aortic valve thickness values obtained through echocardiographic measurements during the ApoA-1 mimetic peptide treatment period.
- Day “0” corresponds to the end of cholesterol plus vitamin D 2 diet and the beginning of ApoA-1 mimetic peptide treatment period, *P ⁇ 0.05; ** ⁇ 0.01., ***P ⁇ 0.001;
- FIG. 4 illustrates a correlation between aortic valve area (AVA) and the percentage of lesion area (LA) over the region of analysis (ROA) in aortic valves from both groups; and
- FIG. 5 illustrates the correlation between aortic valve thickness on echocardiography and the percentage of calcification area in the sinus of Valsalva area in animals from both groups. Note that a value (square) from one control animal is hidden behind two triangles at the bottom left of the figure.
- AVS calcific aortic valve stenosis
- Atherosclerosis and AVS are distinct diseases, affecting different patient populations.
- Apolipoprotein A-I (ApoA-1) is a structural component of HDL that mediates many of its beneficial effects including enhanced reverse cholesterol transport (9).
- the peptide used in our study is capable of forming an amphipathic alpha-helix in the presence of lipids, as is the case for ApoA-1 (10, 11).
- ApoA-1 10, 11
- lipids such as cholesterol and triglycerides.
- cholesterol normally as cholesterol esters
- triglycerides are included into lipoprotein particles in which they form a hydrophobic core.
- the core is surrounded by a surface coat containing phospholipids, unesterified cholesterol and proteins called apolipoproteins.
- the latter are responsible for the lipid transport and, in addition, some may interact with many of the enzymes involved in lipid metabolism.
- at least 10 apolipoproteins have been identified, namely: A-1, A-2, A-4, B-48, B-100, C-I, C-II, C-III, D and E.
- Compound A is a lipoprotein that mimics biologic properties of apolipoprotein A-I (ApoA-1).
- ApoA-1 apolipoprotein A-I mimetic or agonist
- these compounds include peptides, or analogues thereof, which are capable of forming amphipathic alpha-helices in the presence of lipids and which mimic the activity of ApoA-1. They are therefore referred-to as ApoA-1 agonists.
- the agonists have as their main feature a “core” peptide composed of 15 to 29 amino acid residues, preferably 22 amino acid residues, or an analogue thereof wherein at least one amide linkage in the peptide is replaced with a substituted amide, an isostere of an amide or an amide mimetic.
- ApoA-1 agonists are based, in part, on the discovery that altering certain amino acid residues in the primary sequence of the 22-mer consensus sequence disclosed in Venkatachalapathi et al., 1991, Mol. Conformation and Biol. Interactions, Indian Acad. Sci. B: 585-596 (PVLDEFREKLNEELEALKQKLK; hereinafter “Segrest's consensus 22-mer” or “consensus 22-mer”) (SEQ ID NO:2) that were thought to be critical for activity, yields synthetic peptides which exhibit activities that approach, or in some embodiments even exceed, the activity of native ApoA-1.
- Compound A comprises a peptide having the sequence:
- the peptide was complexed with egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (Avanti Polar Lipids) (10) in a 1:1:1 weight ratio by mixing the components in saline and performing multiple heating and cooling cycles until the solution appeared perfectly clear.
- DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
- the solution containing the complexes was lyophilized in aliquots for long-term storage. Fresh solution was reconstituted every week under sterile conditions and kept at 4° C. Biological activity of the complex was tested in rats for its ability to mobilize cholesterol and to raise HDL-cholesterol in blood following an intravenous injection of the peptide (data not shown).
- Suitable compounds disclosed in U.S. Pat. No. 6,376,464 include, but are not limited to, peptides of the following Formula (I)
- X 1 is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
- X 2 is an aliphatic amino acid
- X 3 is Leu (L) or Phe (F);
- X 4 is an acidic amino acid
- X 5 is Leu (L) or Phe (F);
- X 6 is Leu (L) or Phe (F);
- X 7 is a hydrophilic amino acid
- X 8 is an acidic or a basic amino acid
- X 9 is Leu (L) or Gly (G);
- X 10 is Leu (L), Trp (W) or Gly (G);
- X 11 is a hydrophilic amino acid
- X 12 is a hydrophilic amino acid
- X 13 is Gly (G) or an aliphatic amino acid
- X 14 is Leu (L), Trp (W), Gly (G) or Nal;
- X 15 is a hydrophilic amino acid
- X 16 is a hydrophobic amino acid
- X 17 is a hydrophobic amino acid
- X 18 is Gln (Q), Asn (N) or a basic amino acid
- X 19 is Gln (Q), Asn (N) or a basic amino acid
- X 20 is a basic amino acid
- X 21 is an aliphatic amino acid; and X 22 is a basic amino acid.
- the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X 1 is Pro (P), Gly (G), Ala (A), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
- X 2 is Ala (A), Val (V) or Leu (L);
- X 4 is Asp (D) or Glu (E);
- X 7 is Lys (K), Arg (R), Orn, Asn (N) or Glu (E);
- X 8 is Asp (D), Arg (R) or Glu (E);
- X 11 is Asn (N), Gln (Q), Glu (E) or Arg (R);
- X 12 is Asp (D), Glu (E) or Asn (N);
- X 13 is Leu (L), Gly (G) or Aib;
- X 15 is Asp (D), Glu (E), Gln (Q) or Lys (K);
- X 16 is Ala (A), Trp (W), Gly (G), Leu (L), Phe (F) or Nal;
- X 17 is Leu (L), Gly (G) or Nal;
- X 18 is Lys (K), Orn, Gln (Q) or Asn (N);
- X 19 is Lys (K), Orn, Gln (Q) or Asn (N);
- X 20 is Lys (K) or Orn;
- X 21 is Leu (L);
- X 22 is Lys (K) or Orn.
- the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X 2 is Val (V);
- X 3 is Leu (L);
- X 5 is Leu (L);
- X 6 is Phe (F);
- X 7 is Arg (R) or Lys (K);
- X 8 is Glu (E);
- X 9 is Leu (L);
- X 10 is Leu (L);
- X 11 is Asn (N) or Glu (O);
- X 12 is Glu (E);
- X 15 is Glu (E).
- the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X 1 is Pro (P), Gly (G) or D-Pro (p);
- X 2 is Val (V);
- X 3 is Leu (L);
- X 4 is Asp (D) or Glu (E);
- X 5 is L (Leu) or Phe (F);
- X 6 is Phe (F);
- X 7 is Arg (R);
- X 8 is Glu (E);
- X 9 is Leu (L);
- X 10 is Leu (L) or Trp (W);
- X 11 is Asn (N);
- X 12 is Glu (E);
- X 13 is Gly (G);
- X 14 is Leu (L);
- X 15 is Glu (E);
- X 16 is Ala (A) or Trp (W);
- X 17 is Leu (L) or Nal
- X 18 is Lys (K) or Orn;
- X 19 is Gln (Q);
- X 20 is Lys (K) or Orn;
- X 21 is Leu (L).
- X 22 is Lys (K) or Orn.
- the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X 1 is Pro (P), Gly (G), Ala (A) or D-Pro (p);
- X 2 is Val (V) or Leu (L);
- X 3 is Leu (L);
- X 4 is Asp (D) or Glu (E);
- X 5 is Leu (L) or Phe (F);
- X 6 is Leu (L) or Phe (F);
- X 7 is Arg (R) or Lys (K);
- X 8 is Glu (E);
- X 9 is Leu (L);
- X 10 is Leu (L) or Trp (W);
- X 11 is Asn (N) or Gln (Q);
- X 12 is Glu (E);
- X 13 is Leu (L) or Aib
- X 14 is Leu (L), Trp (W) or Nal;
- X 15 is Glu (E);
- X 16 is Ala (A), Leu (L), Trp (W) or Nal;
- X 17 is Leu (L) or Nal; one of X 18 or X 19 is Gln (Q) and the other is Lys (K) or Orn;
- X 20 is Lys (K) or Orn;
- X 21 is Leu (L).
- X 22 is Lys (K) or Orn.
- the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X 2 is Val (V);
- X 4 is Asp (D);
- X 5 is Leu (L);
- X 6 is Phe (F);
- X 7 is Arg R
- X 10 is Leu (L);
- X 11 is Asn (N);
- X 13 is Leu (L);
- X 14 is Leu (L);
- X 16 is Ala (A);
- X 17 is Leu (L);
- X 18 is Lys (K);
- X 19 is Gln (Q);
- X 20 is Lys (K) and/or
- X 22 is Lys (K).
- Compounds of Formula (I) include, for example, peptides of SEQ ID NOS. 3-51, as set forth below.
- PVLDLFRELLNELLEZLKQKLK (SEQ ID NO: 3) GVLDLFRELLNELLEALKQKLKK; (SEQ ID NO: 4) PVLDLFRELLNELLEWLKQKLK; (SEQ ID NO: 5) PVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 6) pVLDLFRELLNELLEALKQKLKK; (SEQ ID NO: 7) PVLDLFRELLNEXLEALKQKLK; (SEQ ID NO: 8) PVLDLFKELLNELLEALKQKLK; (SEQ ID NO: 9) PVLDLFRELLNEGLEALKQKLK; (SEQ ID NO: 10) PVLDLFRELGNELLEALKQKLK; (SEQ ID NO: 11) PVLDLFRELLNELLEAZKQKLK; (SEQ ID NO: 12) PVLDLFKELLQELLEALKQKLK; (SEQ ID NO: 13) PVLDLFRELLNELLEAGKQKLK; (SEQ ID
- Hydrophilic Amino Acid refers to an amino acid exhibiting a hydrophobicity of less than zero according to the normalized consensus hydrophobicity scale of Eisenberg et al., 1984, J. Mol. Biol. 179:125-142. Genetically encoded hydrophilic amino acids include Thr (T), Ser (S), H is (H), Glu (E), Asn (N), Gin (O), Asp (D), Lys (K) and Arg (R).
- Acidic Amino Acid refers to a hydrophilic amino acid having a side chain pK value of less than 7. Acidic amino acids typically have negatively charged side chains at physiological pH due to loss of a hydrogen ion. Genetically encoded acidic amino acids include Glu (E) and Asp (D).
- Basic Amino Acid refers to a hydrophilic amino acid having a side chain pK value of greater than 7.
- Basic amino acids typically have positively charged side chains at physiological pH due to association with hydronium ion.
- Genetically encoded basic amino acids include H is (H), Arg (R) and Lys (K).
- Poly Amino Acid refers to a hydrophilic amino acid having a side chain that is uncharged at physiological pH, but which has at least one bond in which the pair of electrons shared in common by two atoms is held more closely by one of the atoms.
- Genetically encoded polar amino acids include Asn (N), Gin (O) Ser (S) and Thr (T).
- Hydrophobic Amino Acid refers to an amino acid exhibiting a hydrophobicity of greater than zero according to the normalized consensus hydrophobicity scale of Eisenberg, 1984, J. Mol. Biol. 179:1.25-142. Genetically encoded hydrophobic amino acids include Pro (P), Ile (I), Phe (F), Val (V), Leu (L), Trp (W), Met (M), Ala (A), Gly (G) and Tyr (Y).
- “Aliphatic Amino Acid” refers to a hydrophobic amino acid having an aliphatic hydrocarbon side chain. Genetically encoded aliphatic amino acids include Ala (A), Val (V), Leu (L) and Ile (I).
- treating or “treatment” of a state, disease, disorder or condition includes:
- the benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
- subject includes mammals (especially, humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
- domestic animals e.g., household pets including cats and dogs
- non-domestic animals such as wildlife.
- a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
- the “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
- the pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
- a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
- the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
- the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
- suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
- the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
- the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
- compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins).
- the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
- the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
- the active compound can be adsorbed on a granular solid container, for example, in a sachet.
- compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
- the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
- Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
- a complex animal model of aortic valve stenosis has been developed in rabbits.
- the model resulted in aortic valve stenosis characterized by a calcification similar to what is observed in a clinical setting in humans.
- Drolet et al. (12) An animal model adapted from that described by Drolet et al. (12) was used. Fifteen male New-Zealand White rabbits (2.7-3.0 kg, aged 12-13 weeks) were fed with a 0.5% cholesterol-enriched diet (Harlan, Indianapolis, Ind.) plus vitamin D 2 (50000 UI per day; Sigma, Markham, Canada) in the drinking water until significant AVS, as defined by a decrease >10% of aortic valve area (AVA) or of the transvalvular velocities ratio (V1/V 2 ), could be detected by echocardiography (12.9 ⁇ 2.4 weeks).
- AVS aortic valve area
- V1/V 2 transvalvular velocities ratio
- Rabbits were given injections through the marginal ear vein of saline or of the ApoA-1 mimetic peptide (25 mg/kg) complexed with phospholipids (Compound A), 3 times per week for 2 weeks. Echocardiograms were performed serially (see Echocardiography Methods) every 3 to 4 days throughout the randomized treatment period. Two days after their last infusion, the animals underwent a final echocardiogram and were sacrificed, and the aortic valves were harvested for histological analyses.
- Transthoracic echocardiographic studies were performed at baseline, on a weekly basis starting at 8 weeks of hypercholesterolemic diet until significant AVS developed, and then after 4, 7, 10 and 14 days of ApoA-1 mimetic peptide or saline control treatments. Studies were carried out with an S12 probe using a standard echocardiographic system (Sonos 5500, Philips Medical Imaging, Mass.). Intra-muscular injections of ketamine (45 mg/kg) and midazolam (0.75 mg/kg) were used for sedation.
- LVOT left ventricular outflow tract
- CSA LVOT LVOT cross-sectional area
- V1/V2 ratio was calculated in the pre-treatment period to determine AVS development.
- the ascending aorta and aortic valve were opened longitudinally and the 3 valvular cusps were separated.
- Two cusps were immediately frozen in an embedding medium (OCT Tissue-Tek; Sakura, USA) and stored at ⁇ 80° C.
- the third cusp was immersion-fixed in 10% buffered formalin at 4° C. for 24 hours and embedded in paraffin.
- Stained or immunohistochemically labeled tissue sections obtained from the central third of each cusp were analyzed with a computer-based digitizing image system (Image Pro Plus, version 5.1) using a light microscope (BX41, Olympus) connected to a digital video camera (Qcolor3, Olympus).
- the region of analysis (ROA) was composed of 1000 ⁇ m of the Valsalva sinus from the leaflet base and 500 ⁇ m of the leaflet from the leaflet base.
- Lesion area (LA) and leaflet lesion length (LLL) were measured.
- Hematoxylin-phloxin-safran, von Kossa and Sirius red (F3B, BDH, UK) stained sections were prepared for routine examination, tissue calcification and collagen studies respectively. Collagen fibers types I and III were quantified as previously described (13), on Sirius red picric acid stained sections under polarized light. For immunohistochemistry evaluation, all sections were preincubated with either mouse IgG2a monoclonal antibody against rabbit macrophage (RAM11, Dako, Canada) (1:100 dilution) or rabbit smooth muscle cell ⁇ -actin (Clone 1A4, Dako, Canada) (1:200 dilution).
- Species-appropriate biotinylated secondary antibodies were applied, followed by streptavidin horseradish peroxidase complex, visualized with azoethylcarbazol (AEC) and counterstained by Mayer's hematoxylin. Smooth muscle cells, macrophages and calcification areas were quantified in the ROA on digital images acquired at 40 ⁇ magnification. Images from each section were digitally captured with the same illumination settings, and automatic computer-based analysis was performed with the same color threshold for all specimens. Data were expressed as percent labelled area in ROA.
- the group ⁇ time interaction was also included in the ANCOVA models and comparisons between groups ata given time point were undertaken only in the presence of a significant group ⁇ time interaction. Otherwise, global conclusions were drawn based on the main group effects of the model. Histological variables were compared between treated and control groups using Student t-test. Relationships between histomorphometry and echocardiographic variables were evaluated using Pearson correlation coefficient. All analyses were performed with SAS release 8.2 (SAS Institute Inc., Cary, N.C.) and conducted at the 0.05 significance level.
- HDL-cholesterol was 0.50 ⁇ 0.20 mmol/L and 0.50 ⁇ 0.15 mmol/L at the time of randomization and 0.39 ⁇ 0.17 mmol/L and 0.45 ⁇ 0.17 mmol/L at end of treatment.
- AVA decreased in both groups, and values were almost identical between control and treated rabbits (from 24.2 ⁇ 4.1 mm 2 at baseline to 19.0 ⁇ 2.7 mm 2 in controls and from 24.7 ⁇ 3.9 mm 2 to 19.1 ⁇ 2.6 mm 2 in the treated group).
- There were therefore no significant differences in AVA between groups during the period of AVS development (P 0.852).
- AVA decreased by 20.5 ⁇ 4.2% and 21.6 ⁇ 3.7% before randomized treatment in the control and treated groups.
- V 1 /V2 ratio was also significantly different between measurements at baseline and at the end of hypercholesterolemic diet (P ⁇ 0.0001).
- echocardiographic measurements revealed a 21% decrease in AVA.
- Two-dimensional imaging showed increased valve thickness and echogenicity compatible with leaflet sclerosis and areas of calcification. Histological examination confirmed leaflet thickening and calcium deposition both in the sinuses of Valsalva and at the leaflet base. This study provides echocardiographic and histological evidence of the beneficial effects of an ApoA-1 mimetic peptide on experimental calcific AVS.
- AVA Aortic valve thickness was also significantly reduced after only 14 days of treatment with the peptide, as shown by echocardiography. Interestingly, AVA determined by echocardiography correlated inversely with indices of lesion extent on histology.
- ApoA-1 mimetic peptide infusions also led to a significant reduction in the percentage of lesion area in the region of histological analysis around the valvular leaflet base. Furthermore, the large reduction in the extent of valvular calcifications that almost reached statistical significance at the arbitrarily chosen 0.05 level is likely to be of clinical importance, given that calcific AVS of the elderly is the most frequent form of stenosis encountered in developed countries. This suggests that the presence of aortic valve calcifications not only does not preclude obtaining favorable results with the peptide but that this approach may even regress the valvular calcifications themselves. This finding may also be applicable to mitral valve and/or anular calcifications.
- An ApoA-1 mimetic peptide complexed with phospholipids stimulates reverse cholesterol transport in a manner similar to native ApoA-1 (14).
- the higher circulating levels of total cholesterol in rabbits treated with the peptide compared to controls may indicate enhanced mobilization of tissue cholesterol.
- HDL-based therapy such as for example one or more infusion(s) or bolus(es) of HDL or peptide (with or without lipids) with HDL-like effects, orally administered HDL-mimetic agents, and/or the administration of cholesteryl ester transfer protein (CETP) modulators, or scavenger receptor class B, member 1 (SRB1) modulators or liver X receptor (LXR)/retinoid X receptor (RXR) agonists, or ATP-binding cassette transporter-1 (ABCA1) agonists, or peroxisome proliferator-activated receptor (PPAR) agonists, among others.
- CETP cholesteryl ester transfer protein
- SRB1 scavenger receptor class B
- SRB1 scavenger receptor class B
- LXR liver X receptor
- RXR retinoid X receptor
- ABCA1 ATP-binding cassette transporter-1
- PPAR peroxisome proliferator-activated receptor
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Abstract
The present invention provides methods for preventing or treating a valvular stenosis or a valvular calcification in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide/phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide. In one embodiment the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1. In another embodiment the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
Description
- This application is a division of U.S. application Ser. No. 12/227,872, filed on Dec. 1, 2008, which is the national stage of International Application No. PCT/CA2007/000895, filed on May 23, 2007, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/809,850 filed Jun. 1, 2006, the disclosure of each of which is hereby incorporated by reference in its entirety.
- The present invention relates to the general field of medical methods and compounds and is particularly concerned with a method and compound for the treatment of valvular disease.
- The function of the heart is to supply the energy required for the circulation of blood in the cardiovascular system. Blood flow through all organs is passive and occurs only because arterial pressure is kept higher than venous pressure by the pumping action of the heart. The right heart pump provides the energy necessary to move blood through the pulmonary vessels and the left heart pump provides the energy that causes flow through the systemic organs.
- Venous blood returns from the systemic organs to the right atrium via the superior and inferior venae cavae. It passes through the tricuspid valve into the right ventricle and from there is pumped through the pulmonic valve into the pulmonary circulation via the pulmonary arteries. Oxygenated pulmonary venous blood flows in pulmonary veins to the left atrium and passes through the mitral valve into the left ventricle. From there, it is pumped through the aortic valve into the aorta to be distributed to the systemic organs.
- Hence, in its normal operation, the left ventricle of the heart pumps oxygen-rich blood to arteries in the vasculature of the body through the aorta. As the heart pumps, the aortic valve, which is located between the left ventricle and the aorta, opens and closes to control the direction of blood flow. More specifically, during heartbeat or systole, the aortic valve is opened to allow blood to flow from the left ventricle into the aorta. Between heartbeats, or during diastole, however, the aortic valve closes to form a tight seal that prevents blood from leaking back into the ventricle.
- The valves are structurally designed to allow flow in only one direction and passively open and close in response to the direction of the pressure differences across them. Typically, the aortic valve is composed of three fibrous leaflets or cusps. The leaflets are forced open against the walls of the aorta during ventricular ejection of blood but fall back during diastole, their free edges coapting to prevent blood from returning into the heart.
- The aortic wall behind each aortic valve cusp bulges outward, forming three structures known as sinuses of Valsalva. The two most anterior valvular aortic cusps are known as the left and right coronary cusps because of the origin of the left and right coronary arteries from the respective sinuses of Valsalva and the remaining valvular posterior cusp is known as the noncoronary cusp.
- For any of several reasons, it can happen that the aortic valve is somehow damaged and may become stenosed. When this happens, the aortic valve does not open to its normal extent and the flow of blood from the heart into the aorta is hindered. This leads to a heart condition that is commonly known as aortic valve stenosis.
- Common etiologies for aortic valve stenosis include congenital abnormality, rheumatic fever or degeneration with calcification in the aging patient. A bicuspid valve is the most common congenital abnormality, and often a raphe in one of the cusps indicates failure of the commissure to develop. Rarely, a unicuspid or quadricuspid valve can be present at birth. Although the bicuspid valve may not be initially stenotic, fibrosis and thickening lead eventually to reduced orifice size with calcification. Indeed, mechanical sheer stress typically leads to calcific injury.
- Rheumatic fever scars the leaflet margins, and eventually the commissures fuse and calcify. More than 50% of adults with aortic stenosis are found to have a bicuspid valve, but fibrosis and calcification may make it difficult to determine whether the valve is bicuspid or tricuspid.
- In the aging patient with degenerative aortic valve stenosis, calcium deposits usually develop at the sinuses and annulus, whereas the margins of the leaflets often remain free of calcifications.
- Currently, there are many proposed theories for the cellular pathophysiology of aortic valve stenosis. Such theories include cardiovascular risk factors initiating a response to injury, mechanical sheer stress, autoimmune phenomena causing degeneration, chronically raised stroke volume and altered calcium metabolism (such as found in renal failure, Paget's disease, etc.).
- Regardless of its etiology, aortic stenosis produces an increase in systolic left ventricular pressure. Systolic hypertension in the ventricular chamber is compensated by concentric hypertrophy of the myocardial wall, allowing the wall stress to remain normal. The less compliant, thickened left ventricle becomes more dependent on the atrial contribution to diastolic filling, such that left ventricular performance can deteriorate when atrial contraction is lost, for example during atrial fibrillation or atrial-ventricular dissociation. The abnormal relaxation and increased stiffness of the thickened left ventricle during diastole also result in diastolic dysfunction and elevations of left ventricular and left atrial diastolic pressures.
- Myocardial failure can eventually develop from chronic severe valvular obstruction and depression of the contractile state. Left ventricular dilatation can also occur in some patients. Myocardial oxygen consumption remains high owing to elevation of systolic pressure in the left ventricle and increase in left ventricular mass. In addition, the increased left ventricular diastolic pressure reduces the pressure gradient necessary for myocardial perfusion. Thus, significant aortic stenosis creates conditions in which high myocardial oxygen demands are inadequately supported by reduced oxygen supply, which leads to subendocardial ischemia.
- Eventually, with a decline in the inotropic state of the myocardium, the ejection fraction is decreased to below the normal range (with or without associated dilatation of the left ventricle). Further elevation of the left ventricular end diastolic pressure (secondary to diastolic dysfunction with or without systolic dysfunction) results in pulmonary venous hypertension. The increased myocardial oxygen demands in aortic stenosis with the underperfused subendocardial myocardium can produce angina pectoris, arrhythmias, and even sudden death.
- The development of any of the cardinal symptoms in the setting of severe aortic stenosis indicates substantial mortality risk and is an indication for surgical therapy. The average life expectancy after symptom onset is 2-3 years, less if the symptoms are due to heart failure. Because symptoms, and perhaps sudden death, often accompany physical exertion, vigorous activities and competitive sports should be avoided by patients with aortic stenosis, even if it is only mild to moderate in severity. Hence, aortic stenosis is associated not only with high mortality but also with substantial morbidity.
- Calcific aortic stenosis accounts for a large percentage of aortic stenosis cases. The condition is characterized by the build-up of calcified nodules on the upper or superior surface of the aortic valve leaflets. These nodules decrease the flexibility of the leaflets, thereby limiting their mobility and capacity to fully open.
- Three techniques have been employed to correct aortic stenosis, namely valve replacement, intra-operative decalcification or debridement or the heart valve and balloon valvuloplasty.
- Valve replacement, during open-heart surgery, is currently the standard therapy for symptomatic aortic stenosis. Ten-year survival rates for isolated aortic valve replacement are relatively good, even in elderly patients. However, this technique requires the patient to be healthy enough to undergo sternotomy (chest opening) and open heart surgery. The operative mortality for this procedure, particularly in the elderly, is relatively large.
- There are two types of prosthetic heart valves, namely mechanical valves that are composed of only materials that are not derived from living organisms and bio-prosthetic valves that are composed in whole or in part of biological material. Mechanical valves currently in use have a ball-cage construction, a tilted disc construction (1 or 2 discs) or a hinged leaflet construction.
- Bio-prosthetic valves generally comprise a supporting stent and a plurality of leaflets. The leaflets are generally composed of biological material, while the stent, when present, generally comprises non-biological material, at least in part. The biological material of the leaflets can be autologous tissues such as pericardium, fascia lata or cardiac valves. Alternatively, this material can be derived from homologous tissue such as non-autologous human tissue for human implantation or can be xenogeneic.
- Each type of prosthetic heart valve has advantages and disadvantages. Mechanical heart valves are durable and, hence, more likely to result in long-lasting function but require careful chronic anticoagulation because of thrombo-embolic risk. Chronic anticoagulation therapy, however, carries with it a risk of haemorrhage similar in incidence to that of the residual risk for thrombotic events.
- Bio-prosthetic valves initially approximate the haemodynamic properties of the natural valve. They carry a smaller risk of complications secondary to thrombus than do mechanical valves. Such valves, however, carry a significantly higher risk of calcification than mechanical valves. Since treatment of a functionally compromised bio-prosthetic heart valve frequently requires replacement with a new valve (and hence a second open-heart surgery), limitations on the useful life expectancy of a bio-prosthetic heart valve are both a serious medical problem for the patient and a financial drain on the medical system.
- Furthermore, all prosthetic heart valves are somewhat stenotic. Prosthetic dysfunction secondary to thrombosis or calcification can lead to increased obstruction or the development of regurgitation. Regurgitation can also result from a perivalvular leak, that is a leak in the area of the sewing ring of the valve. Turbulence associated with valve dysfunction can cause haemolysis and anemia. Even normally functioning prosthetic valves can cause haemolysis in some patients.
- Endocarditis is another potential and major complication in patients with prosthetic heart valves. Antibiotic prophylaxis has to be administered prior to dental, gastro-intestinal and genito-urinary surgery and other procedures associated with bacteraemia.
- Furthermore, some patients have aortic dimensions that are not large enough to easily accommodate conventional replacement valves. Hence, there is a significant number of patients for whom valve replacement is impossible, impractical, or undesirable.
- Intra-operative mechanical debridement or decalcification of the aortic valve was used for many years prior to the advent of mechanical replacement valves. In this technique, the aorta is entered surgically but, rather than replace the valve manually, the surgeon removes the calcified deposits, using suitable surgical tools. Recently, ultrasonic debridement has also been demonstrated to be effective to remove calcific deposits. Nevertheless, this technique still requires the patient to be healthy enough to survive and recuperate from thoracic surgery, and involves all the costs and risks attendant with such surgery.
- A third technique for correcting aortic stenosis involves percutaneous balloon aortic valvuloplasty. In this procedure, an inflatable balloon catheter is advanced to the aortic valve and inflated to compress and fracture the calcified nodules in an attempt to increase leaflet mobility. Although this procedure eliminates many of the risks and disadvantages attendant with the preceding two techniques, re-stenosis is very common within one year, limiting the usefulness of the technique to temporarily mitigating symptoms for those patients who are poor surgical candidates or refuse surgery.
- Hence, there exists a need for a non-surgical treatment of aortic valve stenosis and other valvular diseases.
- The present invention differs significantly from the prior art and current trends by providing a method for not only preventing the progression of aortic stenosis but also for reducing the degree of stenosis using a reverse lipid transport agonist.
- An object of the present invention is therefore to provide a novel non-surgical treatment of valvular disease.
- In a broad aspect, the invention provides a method for preventing or treating a valvular stenosis in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist. For example, the lipid transport agonist is a reverse cholesterol transport agonist.
- In some embodiments of the invention, the valvular stenosis is an aortic valve stenosis, a calcific valve stenosis, or any other valvular stenosis.
- In some embodiments of the invention, the reverse lipid transport agonist is selected from the group consisting of: an HDL, a peptide with HDL-like physiological effects, a peptide with HDL-like physiological effects complexed to a lipid, an HDL-mimetic agents, a CETP modulator, an SRB1 modulators, an LXR/RXR agonist, an ABCA1 agonists, a PPAR agonist and an Apolipoprotein A-I (ApoA-1) mimetic peptide/phospholipid complex.
- In this latter case, administering the ApoA-1 mimetic peptide/phospholipid complex may include injecting the ApoA-1′ mimetic peptide/phospholipid complex in the subject. Examples of dosages in this case are of from about 1 μg to about 10 g per kg body weight of the subject, about 1 mg to about 0.5 g per kg body weight of the subject, and about 25 mg per kg body weight of the subject.
- For example, the ApoA-1 mimetic peptide has the sequence of SEQ ID NO: 1 found herein below, and the ApoA-1 mimetic peptide may be complexed with egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC).
- In some embodiments, the subject is a mammal, for example a human.
- In another broad aspect, the invention provides a method for preventing or treating a valvular calcification in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist.
- In yet another broad aspect, the invention provides a method for controlling a valvular stenosis in a subject, the method comprising increasing reverse cholesterol transport in a subject in need thereof.
- In yet another broad aspect, the invention provides a method for preventing or reversing valvular stenosis, the method comprising administering to a patient in need thereof a reverse lipid transport agonist.
- In yet another broad aspect, the invention provides a method for controlling a valvular stenosis in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a reverse lipid transport agonist.
- For example, controlling the valvular stenosis may include reducing a rate of progression of the valvular stenosis, or reversing, at least in part, the valvular stenosis.
- In yet another broad aspect, the invention provides the use of a reverse lipid transport agonist for controlling valvular stenosis in a subject.
- In yet another broad aspect, the invention provides the use of a reverse lipid transport agonist for the manufacture of a pharmaceutical composition of matter for controlling valvular stenosis in a subject
- In a variant, the method comprises the administration of a therapeutically effective amount of a compound, referred to hereinafter as compound A, that mimics biologic properties of Apolipoprotein A-1 (ApoA-1). Compound A and other suitable compounds are described in U.S. Pat. Nos. 6,287,590, issued Sep. 11, 2001, and 6,506,799, issued Jan. 14, 2003, which are hereby incorporated by reference in their entirety. Indeed, it is believed that in view of current knowledge regarding the action of the compounds and molecules described in these patents, results similar to those presented herein are obtainable with these compounds and molecules.
- Advantageously, the proposed method replaces relatively invasive or relatively ineffective existing treatments for valvular diseases. Also, in addition to slowing the progression of valvular disease, the proposed method also reverses valvular stenosis. Accordingly, the proposed treatment not only has a potential to slow down or stop the progression of aortic valve stenosis and other valvular diseases, but also to cause the regression of aortic valve stenosis and other valvular diseases.
- Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open-heart surgical valve replacement. To determine if reverse lipid transport agonists have a potential to prevent or treat AVS1 ApoA-1 mimetic peptide infusions were tested to determine if they could induce regression of AVS. To that effect, fifteen New-Zealand White male rabbits received a cholesterol-enriched diet and vitamin D2 until significant AVS was detected by echocardiography. Animals were then randomized to receive saline (control group, n=8) or an ApoA-1 mimetic peptide (treated group, n=7), 3 times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed. Aortic valve area improved significantly in the treated group compared to controls after 7 (21.9±3.6 mm2 vs. 19.6±1.8 mm2, P=0.019) (increases of 14.2% and 3.9%), 10 (23.0±4.1 mm2 vs. 20.3±2.4 mm2, P=0.006)(19.8% vs. 7.6%) and 14 days of treatment (23.8±3.1 mm2 vs. 21.3±2.4 mm2, P=0.012) (24.6% vs. 12.9%). Aortic valve thickness decreased by 21% within 14 days of treatment in the treated group (0.094±0.034 cm vs. 0.075±0.033 cm) whereas it was unchanged in controls (P=0.0006). Lesion extent at the base of valve leaflets and sinuses of Valsalva was smaller in the treated compared to control group (52.8±12.5% vs. 66.7±9.9%, P=0.032). A strong trend towards decreased calcification areas was also observed (1.6±2.0% vs. 6.9±6.7%, P=0.063). Therefore, infusions of ApoA-1 mimetic peptide lead to regression of experimental AVS.
- Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of preferred embodiments thereof, given by way of example only with reference to the accompanying drawings.
- In the appended drawings:
-
FIG. 1 illustrates aortic valve area values obtained through echocardiographic measurements obtained during the ApoA-1 mimetic peptide treatment period. Day “0” corresponds to the end of cholesterol plus vitamin D2 diet and the beginning of ApoA-1 mimetic peptide treatment period, *P<0.05; **P<0.01. (b), Aortic valve thickness values, ***P<0.001; -
FIG. 2 illustrates aortic valve thickness values obtained through echocardiographic measurements during the ApoA-1 mimetic peptide treatment period. Day “0” corresponds to the end of cholesterol plus vitamin D2 diet and the beginning of ApoA-1 mimetic peptide treatment period, *P<0.05; **≦0.01., ***P<0.001; -
FIG. 3 illustrates a comparison of the percentage of lesion area (LA) over the region of analysis (ROA) in aortic valves from control and treated groups, *P=0.032. -
FIG. 4 illustrates a correlation between aortic valve area (AVA) and the percentage of lesion area (LA) over the region of analysis (ROA) in aortic valves from both groups; and -
FIG. 5 illustrates the correlation between aortic valve thickness on echocardiography and the percentage of calcification area in the sinus of Valsalva area in animals from both groups. Note that a value (square) from one control animal is hidden behind two triangles at the bottom left of the figure. - The present description refers to many public documents, the contents of which are hereby incorporated by reference in their entirety. Histopathological, experimental and clinical data suggest that calcific aortic valve stenosis (AVS) is an active disease process with lipoprotein deposition, inflammation and active leaflet calcification (1). Although there are some similarities between AVS and atherosclerosis, their pathophysiology and treatments differ significantly. In terms of pathophysiology, a bicuspid aortic valve is present and contributes to the disease in approximately half the patients with AVS, whereas atherosclerosis is not due to a structural congenital abnormality. Rheumatic heart disease can also lead to AVS, while it has not been linked to atherosclerosis. Calcific AVS of the elderly, the most frequent type in the western countries, often leads to isolated aortic valve replacement without the need for associated coronary bypass surgery. In terms of medical treatments, statins have been shown to be protective in patients with coronary disease and to halt progression or induce regression of atherosclerosis (3); in contrast, the progression of AVS was not prevented by intensive statin therapy in a recent randomized clinical trial (4). Similarly, angiotensin-converting enzyme inhibitors have been shown to be cardioprotective in several large-scale clinical trials but have failed to slow progression of AVS. In summary, atherosclerosis and AVS are distinct diseases, affecting different patient populations.
- There is an inverse relationship between plasma levels of HDL-cholesterol and coronary artery disease. Studies in animals with experimental atherosclerosis have demonstrated that ApoA-1 Milano/phospholipid complexes rapidly mobilize cholesterol and thereby reduce atherosclerotic plaque burden (5, 6). In addition, two clinical studies have suggested that infusions of reconstituted HDL could induce rapid improvement of coronary atherosclerosis (7, 8). We have hypothesized that an HDL-based therapy may also induce regression of AVS. If this could be achieved safely, medical treatment of AVS and its regression may transform our clinical approach of this frequent disease. Apolipoprotein A-I (ApoA-1) is a structural component of HDL that mediates many of its beneficial effects including enhanced reverse cholesterol transport (9). The peptide used in our study is capable of forming an amphipathic alpha-helix in the presence of lipids, as is the case for ApoA-1 (10, 11). We have therefore tested the ability of this ApoA-1 mimetic peptide complexed with phospholipids, mimicking nascent HDL, to induce regression of calcific AVS in a previously described rabbit model (12).
- As is well known, the main function of lipoproteins in plasma is to transport lipids, such as cholesterol and triglycerides. For transport in plasma, cholesterol, normally as cholesterol esters, and the triglycerides are included into lipoprotein particles in which they form a hydrophobic core. The core is surrounded by a surface coat containing phospholipids, unesterified cholesterol and proteins called apolipoproteins. The latter are responsible for the lipid transport and, in addition, some may interact with many of the enzymes involved in lipid metabolism. To date, at least 10 apolipoproteins have been identified, namely: A-1, A-2, A-4, B-48, B-100, C-I, C-II, C-III, D and E.
- We have hypothesized that a strategy directed to increasing the efficiency of the reverse lipid transport mechanism through the use of a suitable compound is a possible approach in the treatment of valvular disease. There is also a possibility that calcific deposits might be removed, thereby effectively curing valvular stenosis.
- The compound used to test this hypothesis, hereinafter referred to as Compound A, is a lipoprotein that mimics biologic properties of apolipoprotein A-I (ApoA-1). This type of compound, an Apo A-I mimetic or agonist, is described in further detail in U.S. Pat. No. 6,376,464 titled “Lipid complexes of APO A-1 agonist compounds,” issued to Dasseux et al. on Apr. 23, 2002. This document is hereby incorporated by reference in its entirety.
- Briefly, these compounds include peptides, or analogues thereof, which are capable of forming amphipathic alpha-helices in the presence of lipids and which mimic the activity of ApoA-1. They are therefore referred-to as ApoA-1 agonists. The agonists have as their main feature a “core” peptide composed of 15 to 29 amino acid residues, preferably 22 amino acid residues, or an analogue thereof wherein at least one amide linkage in the peptide is replaced with a substituted amide, an isostere of an amide or an amide mimetic.
- These ApoA-1 agonists are based, in part, on the discovery that altering certain amino acid residues in the primary sequence of the 22-mer consensus sequence disclosed in Venkatachalapathi et al., 1991, Mol. Conformation and Biol. Interactions, Indian Acad. Sci. B: 585-596 (PVLDEFREKLNEELEALKQKLK; hereinafter “Segrest's consensus 22-mer” or “consensus 22-mer”) (SEQ ID NO:2) that were thought to be critical for activity, yields synthetic peptides which exhibit activities that approach, or in some embodiments even exceed, the activity of native ApoA-1. It was discovered that replacing three charged amino acid residues in Segrest's consensus 22-mer peptide (Glu-5, Lys-9 and Glu-13) with a hydrophobic Leu residue provides peptides that mimic the structural and functional properties of ApoA-1 to a degree that was unprecedented in the art.
- Compound A comprises a peptide having the sequence:
-
(SEQ ID NO: 1) H-Pro-Val-Leu-Asp-Leu-Phe-Arg-Glu-Leu-Leu-Asn- Glu-Leu-Leu-Glu-Ala-Leu-Lys-Gln-Lys-Leu-Lys-OH - and was synthesized by Polypeptide Laboratories (Torrance, Calif., USA). Purity assessed by high performance liquid chromatography and mass spectral analysis was greater than 98%. The peptide was complexed with egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (Avanti Polar Lipids) (10) in a 1:1:1 weight ratio by mixing the components in saline and performing multiple heating and cooling cycles until the solution appeared perfectly clear. The solution containing the complexes was lyophilized in aliquots for long-term storage. Fresh solution was reconstituted every week under sterile conditions and kept at 4° C. Biological activity of the complex was tested in rats for its ability to mobilize cholesterol and to raise HDL-cholesterol in blood following an intravenous injection of the peptide (data not shown).
- Based on their known biological activity and structures, it is believed that other compounds, such as the compounds presented in the above-mentioned U.S. Pat. No. 6,376,464, will show effects similar to Compound A.
- Suitable compounds disclosed in U.S. Pat. No. 6,376,464 include, but are not limited to, peptides of the following Formula (I)
-
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22 - and pharmaceutically acceptable salts thereof, wherein:
- X1 is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
- X2 is an aliphatic amino acid;
- X3 is Leu (L) or Phe (F);
- X4 is an acidic amino acid;
- X5 is Leu (L) or Phe (F);
- X6 is Leu (L) or Phe (F);
- X7 is a hydrophilic amino acid;
- X8 is an acidic or a basic amino acid;
- X9 is Leu (L) or Gly (G);
- X10 is Leu (L), Trp (W) or Gly (G);
- X11 is a hydrophilic amino acid;
- X12 is a hydrophilic amino acid;
- X13 is Gly (G) or an aliphatic amino acid;
- X14 is Leu (L), Trp (W), Gly (G) or Nal;
- X15 is a hydrophilic amino acid;
- X16 is a hydrophobic amino acid;
- X17 is a hydrophobic amino acid;
- X18 is Gln (Q), Asn (N) or a basic amino acid;
- X19 is Gln (Q), Asn (N) or a basic amino acid;
- X20 is a basic amino acid;
- X21 is an aliphatic amino acid; and X22 is a basic amino acid.
- In one embodiment, the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X1 is Pro (P), Gly (G), Ala (A), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
- X2 is Ala (A), Val (V) or Leu (L);
- X4 is Asp (D) or Glu (E);
- X7 is Lys (K), Arg (R), Orn, Asn (N) or Glu (E);
- X8 is Asp (D), Arg (R) or Glu (E);
- X11 is Asn (N), Gln (Q), Glu (E) or Arg (R);
- X12 is Asp (D), Glu (E) or Asn (N);
- X13 is Leu (L), Gly (G) or Aib;
- X15 is Asp (D), Glu (E), Gln (Q) or Lys (K);
- X16 is Ala (A), Trp (W), Gly (G), Leu (L), Phe (F) or Nal;
- X17 is Leu (L), Gly (G) or Nal;
- X18 is Lys (K), Orn, Gln (Q) or Asn (N);
- X19 is Lys (K), Orn, Gln (Q) or Asn (N);
- X20 is Lys (K) or Orn;
- X21 is Leu (L); and/or
- X22 is Lys (K) or Orn.
- In another embodiment, the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X2 is Val (V);
- X3 is Leu (L);
- X5 is Leu (L);
- X6 is Phe (F);
- X7 is Arg (R) or Lys (K);
- X8 is Glu (E);
- X9 is Leu (L);
- X10 is Leu (L);
- X11 is Asn (N) or Glu (O);
- X12 is Glu (E); and/or
- X15 is Glu (E).
- In another embodiment, the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X1 is Pro (P), Gly (G) or D-Pro (p);
- X2 is Val (V);
- X3 is Leu (L);
- X4 is Asp (D) or Glu (E);
- X5 is L (Leu) or Phe (F);
- X6 is Phe (F);
- X7 is Arg (R);
- X8 is Glu (E);
- X9 is Leu (L);
- X10 is Leu (L) or Trp (W);
- X11 is Asn (N);
- X12 is Glu (E);
- X13 is Gly (G);
- X14 is Leu (L);
- X15 is Glu (E);
- X16 is Ala (A) or Trp (W);
- X17 is Leu (L) or Nal;
- X18 is Lys (K) or Orn;
- X19 is Gln (Q);
- X20 is Lys (K) or Orn;
- X21 is Leu (L); and
- X22 is Lys (K) or Orn.
- In another embodiment, the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X1 is Pro (P), Gly (G), Ala (A) or D-Pro (p);
- X2 is Val (V) or Leu (L);
- X3 is Leu (L);
- X4 is Asp (D) or Glu (E);
- X5 is Leu (L) or Phe (F);
- X6 is Leu (L) or Phe (F);
- X7 is Arg (R) or Lys (K);
- X8 is Glu (E);
- X9 is Leu (L);
- X10 is Leu (L) or Trp (W);
- X11 is Asn (N) or Gln (Q);
- X12 is Glu (E);
- X13 is Leu (L) or Aib;
- X14 is Leu (L), Trp (W) or Nal;
- X15 is Glu (E);
- X16 is Ala (A), Leu (L), Trp (W) or Nal;
- X17 is Leu (L) or Nal; one of X18 or X19 is Gln (Q) and the other is Lys (K) or Orn;
- X20 is Lys (K) or Orn;
- X21 is Leu (L); and
- X22 is Lys (K) or Orn.
- In another embodiment, the compound of Formula (I) is a 22 amino acid residue peptide in which:
- X2 is Val (V);
- X4 is Asp (D);
- X5 is Leu (L);
- X6 is Phe (F);
- X7 is Arg R);
- X10 is Leu (L);
- X11 is Asn (N);
- X13 is Leu (L);
- X14 is Leu (L);
- X16 is Ala (A);
- X17 is Leu (L);
- X18 is Lys (K);
- X19 is Gln (Q);
- X20 is Lys (K) and/or
- X22 is Lys (K).
- Compounds of Formula (I) include, for example, peptides of SEQ ID NOS. 3-51, as set forth below.
-
PVLDLFRELLNELLEZLKQKLK; (SEQ ID NO: 3) GVLDLFRELLNELLEALKQKLKK; (SEQ ID NO: 4) PVLDLFRELLNELLEWLKQKLK; (SEQ ID NO: 5) PVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 6) pVLDLFRELLNELLEALKQKLKK; (SEQ ID NO: 7) PVLDLFRELLNEXLEALKQKLK; (SEQ ID NO: 8) PVLDLFKELLNELLEALKQKLK; (SEQ ID NO: 9) PVLDLFRELLNEGLEALKQKLK; (SEQ ID NO: 10) PVLDLFRELGNELLEALKQKLK; (SEQ ID NO: 11) PVLDLFRELLNELLEAZKQKLK; (SEQ ID NO: 12) PVLDLFKELLQELLEALKQKLK; (SEQ ID NO: 13) PVLDLFRELLNELLEAGKQKLK; (SEQ ID NO: 14) GVLDLFRELLNEGLEALKQKLK; (SEQ ID NO: 15) PVLDLFRELLNELLEALOQOLO; (SEQ ID NO: 16) PVLDLFRELWNELLEALKQKLK; (SEQ ID NO: 17) PVLDLLRELLNELLEALKQKLK; (SEQ ID NO: 18) PVLELFKELLQELLEALKQKLK; (SEQ ID NO: 19) GVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 20) pVLDLFRELLNEGLEALKQKLK; (SEQ ID NO: 21) PVLDLFREGLNELLEALKQKLK; (SEQ ID NO: 22) pVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 23) PVLDLFRELLNELLEGLKQKLK; (SEQ ID NO: 24) PLLELFKELLQELLEALKQKLK; (SEQ ID NO: 25) PLLELFKELLQELLEALKQKLK; (SEQ ID NO: 26) PVLDFFRELLNEXLEALKQKLK; (SEQ ID NO: 27) PVLDLFRELLNELLELLKQKLK; (SEQ ID NO: 28) PVLDLFRELLNELZEALKQKLK; (SEQ ID NO: 29) PVLDLFRELLNELWEALKQKLK; (SEQ ID NO: 30) AVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 31) QVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 32) PVLDLFOELLNELLEALOQOLO; (SEQ ID NO: 33) NVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 34) PVLDLFRELLNELGEALKQKLK; (SEQ ID NO: 35) PVLDLFRELLNELLELLKQKLK; (SEQ ID NO: 36) PVLDLFRELLNELLEFLKQKLK; (SEQ ID NO: 37) PVLELFNDLLRELLEALQKKLK; (SEQ ID NO: 38) PVLELFNDLLRELLEALKQKLK; (SEQ ID NO: 39) PVLELFKELLNELLDALRQKLK; (SEQ ID NO: 40) PVLDLFRELLENLLEALQKKLK; (SEQ ID NO: 41) PVLELFERLLEDLLQALNKKLK; (SEQ ID NO: 42) PVLELFERLLEDLLKALNQKLK; (SEQ ID NO: 43) DVLDLFRELLNELLEALKQKLK; (SEQ ID NO: 44) PALELFKDLLQELLEALKQKLK; (SEQ ID NO: 45) PVLDLFRELLNEGLEAZKQKLK; (SEQ ID NO: 46) PVLDLFRELLNEGLEWLKQKLK; (SEQ ID NO: 47) PVLDLFRELWNEGLEALKQKLK; (SEQ ID NO: 48) PVLDLFRELLNEGLEALOQOLO; (SEQ ID NO: 49) PVLDLFRELLNEGLEALQKKLK; (SEQ ID NO: 50) and PVLELFRELLNEGLEALKQKLK. (SEQ ID NO: 51)
wherein X is Aib; Z is Nal; and O is Orn. - As used herein, the abbreviations for the genetically encoded L-enantiomeric amino acids are conventional and are as follows:
-
One-Letter Common Amino Acid Symbol Abbreviation Alanine A Ala Arginine R Arg Asparagine N Asn Aspartic acid D Asp Cysteine C Cys Glutamine Q Gln Glutamic acid E Glu Glycine G Gly Histidine H His Isoleucine I Ile Leucine L Leu Lysine K Lys Phenylalanine F Phe Proline P Pro Serine S Ser Threonine T Thr Tryptophan W Trp Tyrosine Y Tyr Valine V Val - The abbreviations used for the D-enantiomers of the genetically encoded amino acids are lower-case equivalents of the one-letter symbols. For example, “R” designates L-arginine and “r” designates D-arginine.
- “Hydrophilic Amino Acid” refers to an amino acid exhibiting a hydrophobicity of less than zero according to the normalized consensus hydrophobicity scale of Eisenberg et al., 1984, J. Mol. Biol. 179:125-142. Genetically encoded hydrophilic amino acids include Thr (T), Ser (S), H is (H), Glu (E), Asn (N), Gin (O), Asp (D), Lys (K) and Arg (R).
- “Acidic Amino Acid” refers to a hydrophilic amino acid having a side chain pK value of less than 7. Acidic amino acids typically have negatively charged side chains at physiological pH due to loss of a hydrogen ion. Genetically encoded acidic amino acids include Glu (E) and Asp (D).
- “Basic Amino Acid” refers to a hydrophilic amino acid having a side chain pK value of greater than 7. Basic amino acids typically have positively charged side chains at physiological pH due to association with hydronium ion. Genetically encoded basic amino acids include H is (H), Arg (R) and Lys (K).
- “Polar Amino Acid” refers to a hydrophilic amino acid having a side chain that is uncharged at physiological pH, but which has at least one bond in which the pair of electrons shared in common by two atoms is held more closely by one of the atoms. Genetically encoded polar amino acids include Asn (N), Gin (O) Ser (S) and Thr (T).
- “Hydrophobic Amino Acid” refers to an amino acid exhibiting a hydrophobicity of greater than zero according to the normalized consensus hydrophobicity scale of Eisenberg, 1984, J. Mol. Biol. 179:1.25-142. Genetically encoded hydrophobic amino acids include Pro (P), Ile (I), Phe (F), Val (V), Leu (L), Trp (W), Met (M), Ala (A), Gly (G) and Tyr (Y).
- “Aliphatic Amino Acid” refers to a hydrophobic amino acid having an aliphatic hydrocarbon side chain. Genetically encoded aliphatic amino acids include Ala (A), Val (V), Leu (L) and Ile (I).
- The term “treating” or “treatment” of a state, disease, disorder or condition includes:
- (1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;
- (2) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or
- (3) relieving the state, disease, disorder or condition, i.e., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms.
- The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
- The term “subject” includes mammals (especially, humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
- A “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
- Pharmaceutical Compositions
- The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
- Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
- The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
- The pharmaceutical compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
- The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
- The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
- A complex animal model of aortic valve stenosis has been developed in rabbits. The model resulted in aortic valve stenosis characterized by a calcification similar to what is observed in a clinical setting in humans.
- Methods
- Animals and Experiments
- An animal model adapted from that described by Drolet et al. (12) was used. Fifteen male New-Zealand White rabbits (2.7-3.0 kg, aged 12-13 weeks) were fed with a 0.5% cholesterol-enriched diet (Harlan, Indianapolis, Ind.) plus vitamin D2 (50000 UI per day; Sigma, Markham, Canada) in the drinking water until significant AVS, as defined by a decrease >10% of aortic valve area (AVA) or of the transvalvular velocities ratio (V1/V2), could be detected by echocardiography (12.9±2.4 weeks).
- The animals then returned to a standard diet (without vitamin D2) to mimic cholesterol lowering and were randomly assigned to receive either saline (control group, n=8) or the ApoA-1 mimetic peptide (treated group, n=7). Rabbits were given injections through the marginal ear vein of saline or of the ApoA-1 mimetic peptide (25 mg/kg) complexed with phospholipids (Compound A), 3 times per week for 2 weeks. Echocardiograms were performed serially (see Echocardiography Methods) every 3 to 4 days throughout the randomized treatment period. Two days after their last infusion, the animals underwent a final echocardiogram and were sacrificed, and the aortic valves were harvested for histological analyses. Blood samples were obtained through the ear artery at baseline, prior to treatment and before sacrifice. Total cholesterol, HDL cholesterol, triglycerides and calcium levels were measured with an automated filter photometer system (Dimension RxL Max, Dade Behring, Ill.).
- Animal care and procedures complied with the Canadian Council on Animal Care guidelines and were approved by the institutional ethics committee for animal research.
- Echocardiography
- Transthoracic echocardiographic studies were performed at baseline, on a weekly basis starting at 8 weeks of hypercholesterolemic diet until significant AVS developed, and then after 4, 7, 10 and 14 days of ApoA-1 mimetic peptide or saline control treatments. Studies were carried out with an S12 probe using a standard echocardiographic system (Sonos 5500, Philips Medical Imaging, Mass.). Intra-muscular injections of ketamine (45 mg/kg) and midazolam (0.75 mg/kg) were used for sedation.
- Parasternal long and short-axis views of the aortic valve were recorded to assess leaflet morphology. Left ventricular outflow tract (LVOT) diameter was measured in a zoomed parasternal long-axis view, and LVOT cross-sectional area (CSALVOT) was calculated according to: CSALVOT=TT (DLVOT/2)2. LVOT velocity (V1) and velocity time integral (VTILVOT) were obtained with pulsed-wave Doppler sampled proximal to the aortic valve in the apical 5-chamber view. Continuous wave (CW) Doppler interrogation across the aortic valve was used to obtain transvalvular maximal velocity (V2) and VTI (VTIAO) in the same view. V1/V2 ratio was calculated in the pre-treatment period to determine AVS development. Aortic valve area (AVA) was obtained at each time point by the continuity equation: AVA=CSALVOT×(VTILVOT/VTIAO)—Aortic valve thickness in its middle portion was measured at end-diastole in a zoomed parasternal long-axis view at baseline, before randomized therapy, and at the final echocardiographic exam.
- The average of three consecutive cardiac cycles was used for each measurement. Special care was taken to obtain similar imaging planes on serial examinations by reviewing previous recordings before follow-up study. All echocardiographic imaging and measurements were performed throughout the protocol by the same experienced investigator blinded to randomized treatment assignment.
- Histomorphometry
- The ascending aorta and aortic valve were opened longitudinally and the 3 valvular cusps were separated. Two cusps were immediately frozen in an embedding medium (OCT Tissue-Tek; Sakura, USA) and stored at −80° C. The third cusp was immersion-fixed in 10% buffered formalin at 4° C. for 24 hours and embedded in paraffin. Stained or immunohistochemically labeled tissue sections obtained from the central third of each cusp were analyzed with a computer-based digitizing image system (Image Pro Plus, version 5.1) using a light microscope (BX41, Olympus) connected to a digital video camera (Qcolor3, Olympus). The region of analysis (ROA) was composed of 1000 μm of the Valsalva sinus from the leaflet base and 500 μm of the leaflet from the leaflet base. Lesion area (LA) and leaflet lesion length (LLL) were measured.
- Histochemistry
- Hematoxylin-phloxin-safran, von Kossa and Sirius red (F3B, BDH, UK) stained sections were prepared for routine examination, tissue calcification and collagen studies respectively. Collagen fibers types I and III were quantified as previously described (13), on Sirius red picric acid stained sections under polarized light. For immunohistochemistry evaluation, all sections were preincubated with either mouse IgG2a monoclonal antibody against rabbit macrophage (RAM11, Dako, Canada) (1:100 dilution) or rabbit smooth muscle cell α-actin (Clone 1A4, Dako, Canada) (1:200 dilution). Species-appropriate biotinylated secondary antibodies were applied, followed by streptavidin horseradish peroxidase complex, visualized with azoethylcarbazol (AEC) and counterstained by Mayer's hematoxylin. Smooth muscle cells, macrophages and calcification areas were quantified in the ROA on digital images acquired at 40× magnification. Images from each section were digitally captured with the same illumination settings, and automatic computer-based analysis was performed with the same color threshold for all specimens. Data were expressed as percent labelled area in ROA.
- For assessment of tissue free cholesterol, 5 μm cryosections fixed in 4% paraformaldehyde in PBS (pH 7.4) were stained with filipin (13). Sections were incubated for 1 hour at room temperature in filipin complex (Sigma, Canada) dissolved in DMSO and diluted in PBS, mounted in Vectashield (Vector Laboratories, USA) and viewed by fluorescence microscopy using a Zeiss Axiovert 200M microscope with the DAPI filter set. Images were acquired with an AxioCam MRm digital camera mounted with a 0.63× C-mount adapter. Filipin data were expressed as arbitrary units of fluorescence intensity.
- Statistical Analysis
- Data are presented as mean±standard deviation. For the “pre-treatment” period, repeated measures analysis of variance (ANOVA) models were used to study the echocardiographic and serum measurements across time and between groups (treated vs. control groups). Models with time, group and group×time interaction as independent variables were used and comparisons between groups at a given time point were undertaken only in the presence of a significant group×time interaction. Otherwise, global conclusions were drawn based on the main group effects of the model. For the randomized treatment period, repeated measures analysis of covariance (ANCOVA) models were used to study the echocardiographic and serum measurements across time and between groups (treated vs. control groups), adjusted for the baseline value of the response variable. The group×time interaction was also included in the ANCOVA models and comparisons between groups ata given time point were undertaken only in the presence of a significant group×time interaction. Otherwise, global conclusions were drawn based on the main group effects of the model. Histological variables were compared between treated and control groups using Student t-test. Relationships between histomorphometry and echocardiographic variables were evaluated using Pearson correlation coefficient. All analyses were performed with SAS release 8.2 (SAS Institute Inc., Cary, N.C.) and conducted at the 0.05 significance level.
- Results
- Serum Lipids and Calcemia
- There was no significant difference between groups during the pre-treatment period (the hypercholesterolemic diet period) for serum levels of total cholesterol (P=0.942), HDL-cholesterol (P=0.787), triglycerides (P=O.906), and calcemia (P=0.727). During the 2-week treatment period, total cholesterol levels were also statistically similar in both groups (P=0.470). Values were 20.46±3.52 mmol/L and 20.13±5.18 mmol/L at the time of randomization and 13.78±6.24 mmol/L and 17.57±10.32 mmol/L at end of treatment in the control and treated groups respectively. There was no statistically significant difference between groups for HDL-cholesterol levels during the treatment period (P=0.374). HDL-cholesterol was 0.50±0.20 mmol/L and 0.50±0.15 mmol/L at the time of randomization and 0.39±0.17 mmol/L and 0.45±0.17 mmol/L at end of treatment. During this period, triglyceride levels were also similar (P=O.544). There was no significant difference between groups for calcemia during the treatment period (P=0.832), with values of 3.31±0.29 mmol/L and 3.15±0.37 mmol/L before randomization and 3.22±0.11 mmol/L and 3.22±0.12 mmol/L at the end of treatment in both groups.
- Development of AVS During the Period of Hypercholesterolemic Diet and Vitamin D2 Supplementation
- AVS induction time by the cholesterol plus vitamin D2 diet was similar for control and treated groups (12.8±2.2 vs. 13.0±2.9 weeks; P=0.852). There was a significant difference between AVA at baseline and at the end of the hypercholesterolemic diet period (P<0.0001). AVA decreased in both groups, and values were almost identical between control and treated rabbits (from 24.2±4.1 mm2 at baseline to 19.0±2.7 mm2 in controls and from 24.7±3.9 mm2 to 19.1±2.6 mm2 in the treated group). There were therefore no significant differences in AVA between groups during the period of AVS development (P=0.852). Thus, AVA decreased by 20.5±4.2% and 21.6±3.7% before randomized treatment in the control and treated groups.
- The V1/V2 ratio was also significantly different between measurements at baseline and at the end of hypercholesterolemic diet (P<0.0001). V1ZV2 ratios decreased between these time points with no significant differences among groups (P=0.914).
- Evolution of AVS With Treatment-Echocardiography
- As illustrated in
FIG. 1 , during the treatment period (from AVS detection to after 2 weeks of treatment), significant group×time interaction was observed for AVA (P=0.013). Using repeated measures ANCOVA models, echocardiographic measurements revealed significant increases of AVA in the treated group as compared to controls after 7 days (21.9±3.6 mm2 vs. 19.6H 0.8 mm2, P=0.019) (relative increases of 14.2±3.5% vs. 3.9+3.4%), 10 days (23.0±4.1 mm2 vs. 20.3±2.4 mm2, P=0.006) (relative increases of 19.8+3.5% vs. 7.6±4.2%) and 14 days of treatment (23.8±3.1 mm2 vs. 21.3±2.4 mm2, P=0.012) (relative increases of 24.6±2.0% vs. 12.9+3.5%). - Aortic valve thickness was assessed by echocardiography and measured before randomized therapy and after 14 days of treatment. Significant group×time interaction was also observed for aortic valve thickness (P=0.005). No significant difference was found between groups at the randomization time point but a significant decrease of aortic valve thickness was observed in the treated group as compared to the control group after 14 days of treatment. Aortic valve thickness was 0.094±0.034 cm before randomization and 0.075±0.033 cm at end of treatment in treated rabbits whereas it was 0.080±0.024 cm and 0.080+0.026 cm at both time points in controls.
- Histology
- All the animals presented aortic valve lesions. Lesions consisted in a cap of neotissue composed of multiple layers of foam cells giving place gradually, to fibrotic material sparse with foam cells from about half-way deep in the lesion. Lesions were generally progressing from the sinotubular area, covering the whole sinus of Valsalva and extending to the cusp base and up to one half to two thirds of the proximal leaflet arterialis. In contrast, lesions on the leaflet ventricularis were not common and were less severe.
- Histomorphometry
- As shown in
FIG. 3 the percentage of LA per ROA decreased significantly in the ApoA-1 mimetic peptide treated group as compared to the control group (52.8±12.5%/ROA vs. 66.7±9.9%/ROA, P=0.032). Interestingly, when the percentage of LA/ROA on histomorphometry and echocardiography-determined AVA from both groups were pooled, a negative correlation was found between the percentage of LA/ROA and AVA (r=−0.54, P=0.039,FIG. 4 . Similarly, analysis of pooled data from both groups revealed a negative correlation between AVA and % LLL (Ae. the percentage of total leaflet length occupied by lesion or LLL/total leaflet length×100) (r=−0.70, P=0.004). However, the difference between the treated and control groups for % LLL did not reach statistical significance (55.7±24.3% vs. 72.3±11.7%, P=0.109). - Histochemistry
- Foci of calcifications were observed in the majority of animals The percentages of rabbits with calcium deposits in the lesion core in the sinuses of Valsalva were 57% ( 4/7) in the treated group and 88% (⅞) in controls. Quantification of the percentage of the sinus of Valsalva area occupied by calcifications on von Kossa staining revealed a strong trend towards a 77% decrease in the treated group compared to controls (1.6±2.0% vs. 6.9+6.7%; P=0.063). This percentage of calcification foci area within the sinus area was significantly correlated with echocardiography-determined aortic valve thickness (r=0.63, P=0.012) using pooled data from both study groups (
FIG. 5 ). - Free cholesterol, as detected by filipin staining, was present throughout the whole aortic valve lesion areas in almost all control animals, whereas the fluorescent signal tended to be lower at the luminal edge of lesions in most animals treated with the ApoA-1 mimetic peptide. Assessment of the fluorescent signal within the first 10 μm at the luminal edge of lesions showed a 41% decrease in free cholesterol in treated animals compared to controls but this difference did not reach statistical significance (221±54 vs. 377±229 arbitrary units of fluorescence intensity, P=0.231). The macrophage areas (34.5%) were about twice as large as α-actin positive areas (17.1%), with no significant differences between groups. The percentage of collagen type III fibers (light green) was higher than collagen type I fibers (red-yellow) in the ROA (19.7+5.5%/ROA for type III vs. 6.6±4.1%/ROA for type I in controls, P=0.00009; 19.1+11.3%/ROA for type III vs. 5.5±5.6%/ROA for type I in treated rabbits, P=0.015,). Percentages of collagen fibers (types I and III) in the ROA were however similar between both groups (P=0.671 and P=0.883 respectively).
- Discussion
- These experiments demonstrate that infusions of an ApoA-1 mimetic peptide lead to significant regression of experimental AVS. Compared to the control group, ApoA-1 mimetic peptide infusions induced greater improvement of AVA and a significant reduction in aortic valve thickness. These favorable changes in AVS severity on echocardiography were accompanied on histological sections by a significant decrease in lesion extent in the leaflet base region and a strong trend towards decreased calcifications.
- A rabbit model of AVS developed by Drolet et al. (12) in which aortic valve calcification occurs significantly and reproducibly was used, allowing to mimic the clinical condition. After a cholesterol-enriched diet and vitamin D2 supplementation for approximately 13 weeks, echocardiographic measurements revealed a 21% decrease in AVA. Two-dimensional imaging showed increased valve thickness and echogenicity compatible with leaflet sclerosis and areas of calcification. Histological examination confirmed leaflet thickening and calcium deposition both in the sinuses of Valsalva and at the leaflet base. This study provides echocardiographic and histological evidence of the beneficial effects of an ApoA-1 mimetic peptide on experimental calcific AVS. The increase in AVA was observed as early as 7 days after the initiation of active treatment, to reach an improvement of 24% at 14 days. AVA indeed almost returned, with the ApoA-1 mimetic peptide infusions, to the normal value present prior to starting the hypercholesterolemic diet. In contrast, discontinuation of the cholesterol-enriched diet with vitamin D2 supplementation in the control group (to mimic lipid-lowering) only led to a mild increase in AVA1 which confirms the beneficial effects of the peptide. Aortic valve thickness was also significantly reduced after only 14 days of treatment with the peptide, as shown by echocardiography. Interestingly, AVA determined by echocardiography correlated inversely with indices of lesion extent on histology. ApoA-1 mimetic peptide infusions also led to a significant reduction in the percentage of lesion area in the region of histological analysis around the valvular leaflet base. Furthermore, the large reduction in the extent of valvular calcifications that almost reached statistical significance at the arbitrarily chosen 0.05 level is likely to be of clinical importance, given that calcific AVS of the elderly is the most frequent form of stenosis encountered in developed countries. This suggests that the presence of aortic valve calcifications not only does not preclude obtaining favorable results with the peptide but that this approach may even regress the valvular calcifications themselves. This finding may also be applicable to mitral valve and/or anular calcifications.
- An ApoA-1 mimetic peptide complexed with phospholipids stimulates reverse cholesterol transport in a manner similar to native ApoA-1 (14). The higher circulating levels of total cholesterol in rabbits treated with the peptide compared to controls (observed after 2 weeks of treatment) may indicate enhanced mobilization of tissue cholesterol.
- This example suggests that similar results are obtainable in humans using any suitable HDL-based therapy, such as for example one or more infusion(s) or bolus(es) of HDL or peptide (with or without lipids) with HDL-like effects, orally administered HDL-mimetic agents, and/or the administration of cholesteryl ester transfer protein (CETP) modulators, or scavenger receptor class B, member 1 (SRB1) modulators or liver X receptor (LXR)/retinoid X receptor (RXR) agonists, or ATP-binding cassette transporter-1 (ABCA1) agonists, or peroxisome proliferator-activated receptor (PPAR) agonists, among others.
- While the experiments described herein concerned the regulation aortic valve stenosis, one of ordinary skilled in the art will readily appreciate that these experiments may be predictive of biological effects in humans or other mammals and/or may serve as models for use of the present invention in humans or other mammals for any other similar valve diseases.
- Although the present invention has been described hereinabove by way of preferred embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claim.
-
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- 7. Nissen S E, Tsunoda T, Tuzcu E M, et al. Effect of recombinant ApoA-1 Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290:2292-300.
- 8. Tardif J C, Gregoire J, L'Allier P L, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007,297: 1675-82.
- 9. Meyers C D, Kashyap M L. Pharmacologic augmentation of high-density lipoproteins: mechanisms of currently available and emerging therapies. Curr Opin Cardiol 2005, 20:307-12.
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- 11. Bodary P F, Shen Y, Westrick R J, et al. Gene transfer of an APO-A-I mimetic peptide reduces atherosclerosis in mice. J Am Coll Cardiol. 2004; 43(Suppl A):465A-6.
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Claims (49)
1-23. (canceled)
24. A method for preventing or treating a valvular stenosis in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide/phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide.
25. The method of claim 24 , wherein said valvular stenosis is an aortic valve stenosis.
26. The method of claim 24 , wherein said valvular stenosis is a calcific valve stenosis.
27. The method of claim 24 , wherein administering said peptide/phospholipid complex includes injecting said peptide/phospholipid complex in said subject.
28. The method of claim 27 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 μg to about 10 g of peptide per kg body weight of said subject.
29. The method of claim 28 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 mg to about 0.5 g of peptide per kg body weight of said subject.
30. The method of claim 29 , wherein said peptide/phospholipid complex is injected at a dosage of about 25 mg of peptide per kg body weight of said subject.
31. The method of claim 24 , wherein said subject is a mammal.
32. The method of claim 31 , wherein said subject is a human.
33. The method of claim 24 , wherein the valvular stenosis is prevented.
34. The method of claim 24 , wherein the valvular stenosis is treated.
35. The method of claim 24 , wherein treating said valvular stenosis includes reducing a rate of progression of said valvular stenosis.
36. The method of claim 24 , wherein the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof.
37. The method of claim 24 , wherein the Apolipoprotein A-1 mimetic peptide has a sequence set forth in one of SEQ ID NOS: 3 to 51 or a pharmaceutically acceptable salt thereof.
38. The method of claim 24 , wherein the Apolipoprotein A-1 mimetic peptide is a peptide of the following Formula (I)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22
or a pharmaceutically acceptable salt thereof, wherein:
Xi is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
X2 is an aliphatic amino acid;
X3 is Leu (L) or Phe (F);
X4 is an acidic amino acid;
X5 is Leu (L) or Phe (F);
X6 is Leu (L) or Phe (F);
X7 is a hydrophilic amino acid;
X8 is an acidic or a basic amino acid;
X9 is Leu (L) or Gly (G);
X10 is Leu (L), Trp (W) or Gly (G);
X11 is a hydrophilic amino acid;
X12 is a hydrophilic amino acid;
X13 is Gly (G) or an aliphatic amino acid;
X14 is Leu (L), Trp (W), Gly (G) or Nal;
X15 is a hydrophilic amino acid;
X16 is a hydrophobic amino acid;
X17 is a hydrophobic amino acid;
X18 is Gln (Q), Asn (N) or a basic amino acid;
X19 is Gln (Q), Asn (N) or a basic amino acid;
X20 is a basic amino acid;
X21 is an aliphatic amino acid; and
X22 is a basic amino acid.
39. The method of claim 38 , wherein:
X1 is Pro (P), Gly (G), Ala (A), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
X2 is Ala (A), Val (V) or Leu (L);
X4 is Asp (D) or Glu (E);
X7 is Lys (K), Arg (R), Orn, Asn (N) or Glu (E);
X8 is Asp (D), Arg (R) or Glu (E);
X11 is Asn (N), Gln (Q), Glu (E) or Arg (R);
X12 is Asp (D), Glu (E) or Asn (N);
X13 is Leu (L), Gly (G) or Aib;
X15 is Asp (D), Glu (E), Gln (Q) or Lys (K);
X16 is Ala (A), Trp (W), Gly (G), Leu (L), Phe (F) or Nal;
X17 is Leu (L), Gly (G) or Nal;
X18 is Lys (K), Orn, Gln (Q) or Asn (N);
X19 is Lys (K), Orn, Gln (Q) or Asn (N);
X20 is Lys (K) or Orn;
X21 is Leu (L); and/or
X22 is Lys (K) or Orn.
40. The method of claim 38 , wherein:
X2 is Val (V);
X3 is Leu (L);
X5 is Leu (L);
X6 is Phe (F);
X7 is Arg (R) or Lys (K);
X8 is Glu (E);
X9 is Leu (L);
X10 is Leu (L);
Xii is Asn (N) or Glu (O);
X12 is Glu (E); and/or
X15 is Glu (E).
41. The method of claim 38 , wherein:
X1 is Pro (P), Gly (G) or D-Pro (p);
X2 is Val (V);
X3 is Leu (L);
X4 is Asp (D) or Glu (E);
X5 is L (Leu) or Phe (F);
X6 is Phe (F);
X7 is Arg (R);
X8 is Glu (E);
X9 is Leu (L);
X10 is Leu (L) or Trp (W);
X11 is Asn (N);
X12 is Glu (E);
X13 is Gly (G);
X14 is Leu (L);
X15 is Glu (E);
X16 is Ala (A) or Trp (W);
X17 is Leu (L) or Nal;
X18 is Lys (K) or Orn;
X19 is Gln (Q);
X20 is Lys (K) or Orn;
X21 is Leu (L); and
X22 is Lys (K) or Orn.
42. The method of claim 38 , wherein:
Xi is Pro (P), Gly (G), Ala (A) or D-Pro (p);
X2 is Val (V) or Leu (L);
X3 is Leu (L);
X4 is Asp (D) or Glu (E);
X5 is Leu (L) or Phe (F);
X6 is Leu (L) or Phe (F);
X7 is Arg (R) or Lys (K);
X8 is Glu (E);
X9 is Leu (L);
X10 is Leu (L) or Trp (W);
X11 is Asn (N) or Gln (Q);
X12 is Glu (E);
X13 is Leu (L) or Aib;
X14 is Leu (L), Trp (W) or Nal;
X15 is Glu (E);
X16 is Ala (A), Leu (L), Trp (W) or Nal;
X17 is Leu (L) or Nal;
one of X18 or X19 is Gln (Q) and the other is Lys (K) or Orn;
X20 is Lys (K) or Orn;
X21 is Leu (L); and
X22 is Lys (K) or Orn.
43. The method of claim 38 , wherein:
X2 is Val (V);
X4 is Asp (D);
X5 is Leu (L);
X6 is Phe (F);
X7 is Arg R);
X10 is Leu (L);
Xii is Asn (N);
X13 is Leu (L);
X14 is Leu (L);
X16 is Ala (A);
X17 is Leu (L);
X18 is Lys (K);
X19 is Gln (Q);
X20 is Lys (K) and/or
X22 is Lys (K).
44. The method of claim 24 , wherein the phospholipid of the complex is egg sphingomyelin or 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
45. The method of claim 24 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
46. The method of claim 45 , wherein the egg sphingomyelin and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1.
47. The method of claim 36 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
48. The method of claim 47 , wherein the peptide of SEQ. ID. NO: 1 or pharmaceutically acceptable salt thereof, the egg sphingomyelin, and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1:1.
49. A method for preventing or treating a valvular calcification in a subject, said method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide/phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide.
50. The method of claim 49 , wherein administering said peptide/phospholipid complex includes injecting said peptide/lipid complex in said subject.
51. The method of claim 50 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 μg to about 10 g of peptide per kg body weight of said subject.
52. The method of claim 51 , wherein said peptide/phospholipid complex is injected at a dosage of from about 1 mg to about 0.5 g of peptide per kg body weight of said subject.
53. The method of claim 52 , wherein said peptide/phospholipid complex is injected at a dosage of about 25 mg of peptide per kg body weight of said subject.
54. The method of claim 49 , wherein said subject is a mammal.
55. The method of claim 54 , wherein said subject is a human.
56. The method of claim 49 , wherein the valvular calcification is prevented.
57. The method of claim 49 , wherein the valvular calcification is treated.
58. The method of claim 49 , wherein treating said valvular calcification includes reducing a rate of progression of said valvular calcification.
59. The method of claim 49 , wherein the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof.
60. The method of claim 49 , wherein the Apolipoprotein A-1 mimetic peptide has a sequence set forth in one of SEQ ID NOS: 3 to 51 or a pharmaceutically acceptable salt thereof.
61. The method of claim 49 , wherein the Apolipoprotein A-1 mimetic peptide is a peptide of the following Formula (I))
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22
or a pharmaceutically acceptable salt thereof, wherein:
Xi is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
X2 is an aliphatic amino acid;
X3 is Leu (L) or Phe (F);
X4 is an acidic amino acid;
X5 is Leu (L) or Phe (F);
X6 is Leu (L) or Phe (F);
X7 is a hydrophilic amino acid;
X8 is an acidic or a basic amino acid;
X9 is Leu (L) or Gly (G);
X10 is Leu (L), Trp (W) or Gly (G);
X11 is a hydrophilic amino acid;
X12 is a hydrophilic amino acid;
X13 is Gly (G) or an aliphatic amino acid;
X14 is Leu (L), Trp (W), Gly (G) or Nal;
X15 is a hydrophilic amino acid;
X16 is a hydrophobic amino acid;
X17 is a hydrophobic amino acid;
X18 is Gln (Q), Asn (N) or a basic amino acid;
X19 is Gln (Q), Asn (N) or a basic amino acid;
X20 is a basic amino acid;
X21 is an aliphatic amino acid; and
X22 is a basic amino acid.
62. The method of claim 61 , wherein:
X1 is Pro (P), Gly (G), Ala (A), Gln (Q), Asn (N), Asp (D) or D-Pro (p);
X2 is Ala (A), Val (V) or Leu (L);
X4 is Asp (D) or Glu (E);
X7 is Lys (K), Arg (R), Orn, Asn (N) or Glu (E);
X8 is Asp (D), Arg (R) or Glu (E);
X11 is Asn (N), Gln (Q), Glu (E) or Arg (R);
X12 is Asp (D), Glu (E) or Asn (N);
X13 is Leu (L), Gly (G) or Aib;
X15 is Asp (D), Glu (E), Gln (Q) or Lys (K);
X16 is Ala (A), Trp (W), Gly (G), Leu (L), Phe (F) or Nal;
X17 is Leu (L), Gly (G) or Nal;
X18 is Lys (K), Orn, Gln (Q) or Asn (N);
X19 is Lys (K), Orn, Gln (Q) or Asn (N);
X20 is Lys (K) or Orn;
X21 is Leu (L); and/or
X22 is Lys (K) or Orn.
63. The method of claim 61 , wherein:
X2 is Val (V);
X3 is Leu (L);
X5 is Leu (L);
X6 is Phe (F);
X7 is Arg (R) or Lys (K);
X8 is Glu (E);
X9 is Leu (L);
X10 is Leu (L);
Xii is Asn (N) or Glu (Q);
X12 is Glu (E); and/or
X15 is Glu (E).
64. The method of claim 61 , wherein:
X1 is Pro (P), Gly (G) or D-Pro (p);
X2 is Val (V);
X3 is Leu (L);
X4 is Asp (D) or Glu (E);
X5 is L (Leu) or Phe (F);
X6 is Phe (F);
X7 is Arg (R);
X8 is Glu (E);
X9 is Leu (L);
X10 is Leu (L) or Trp (W);
X11 is Asn (N);
X12 is Glu (E);
X13 is Gly (G);
X14 is Leu (L);
X15 is Glu (E);
X16 is Ala (A) or Trp (W);
X17 is Leu (L) or Nal;
X18 is Lys (K) or Orn;
X19 is Gln (Q);
X20 is Lys (K) or Orn;
X21 is Leu (L); and
X22 is Lys (K) or Orn.
65. The method of claim 61 , wherein:
Xi is Pro (P), Gly (G), Ala (A) or D-Pro (p);
X2 is Val (V) or Leu (L);
X3 is Leu (L);
X4 is Asp (D) or Glu (E);
X5 is Leu (L) or Phe (F);
X6 is Leu (L) or Phe (F);
X7 is Arg (R) or Lys (K);
X8 is Glu (E);
X9 is Leu (L);
X10 is Leu (L) or Trp (W);
X11 is Asn (N) or Gln (Q);
X12 is Glu (E);
X13 is Leu (L) or Aib;
X14 is Leu (L), Trp (W) or Nal;
X15 is Glu (E);
X16 is Ala (A), Leu (L), Trp (W) or Nal;
X17 is Leu (L) or Nal;
one of X18 or X19 is Gln (Q) and the other is Lys (K) or Orn;
X20 is Lys (K) or Orn;
X21 is Leu (L); and
X22 is Lys (K) or Orn.
66. The method of claim 61 , wherein:
X2 is Val (V);
X4 is Asp (D);
X5 is Leu (L);
X6 is Phe (F);
X7 is Arg R);
X10 is Leu (L);
Xii is Asn (N);
X13 is Leu (L);
X14 is Leu (L);
X16 is Ala (A);
X17 is Leu (L);
X18 is Lys (K);
X19 is Gln (Q);
X20 is Lys (K) and/or
X22 is Lys (K).
67. The method of claim 49 , wherein the phospholipid of the complex is egg sphingomyelin or 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
68. The method of claim 49 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
69. The method of claim 49 , wherein the egg sphingomyelin and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1.
70. The method of claim 59 , wherein the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.
71. The method of claim 70 , wherein the peptide of SEQ. ID. NO: 1 or pharmaceutically acceptable salt thereof, the egg sphingomyelin, and the 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine are present in a weight ratio of 1:1:1.
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US22787208A | 2008-12-01 | 2008-12-01 | |
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US12/227,872 Expired - Fee Related US8163699B2 (en) | 2006-06-01 | 2007-05-23 | Method for the treatment of valvular disease |
US12/956,615 Abandoned US20110092430A1 (en) | 2006-06-01 | 2010-11-30 | Method and compound for the treatment of valvular disease |
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US12/227,872 Expired - Fee Related US8163699B2 (en) | 2006-06-01 | 2007-05-23 | Method for the treatment of valvular disease |
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US (2) | US8163699B2 (en) |
EP (2) | EP2026829B1 (en) |
JP (2) | JP5394236B2 (en) |
CN (1) | CN101489577B (en) |
CA (1) | CA2653840A1 (en) |
ES (1) | ES2402823T3 (en) |
HK (1) | HK1129585A1 (en) |
MX (1) | MX2008015337A (en) |
WO (1) | WO2007137400A1 (en) |
Cited By (2)
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---|---|---|---|---|
US20090186808A1 (en) * | 2006-06-01 | 2009-07-23 | Jean-Claude Tardif | Method and Compound for the Treatment of Valvular Disease |
US20100267631A1 (en) * | 2009-02-16 | 2010-10-21 | Jean-Louis Dasseux | Apolipoprotein a-i mimics |
Families Citing this family (10)
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US8206750B2 (en) | 2005-03-24 | 2012-06-26 | Cerenis Therapeutics Holding S.A. | Charged lipoprotein complexes and their uses |
WO2010083611A1 (en) * | 2009-01-23 | 2010-07-29 | Institut De Cardiologie De Montreal | Method for the prevention and treatment of diastolic dysfunction employing an apolipoproteina1 (apoa1) mimetic peptide/phospholipid complex |
US20130197226A1 (en) * | 2010-07-28 | 2013-08-01 | Jean-Claude Tardif | Pharmaceutical compositions for the treatment of left ventricular diastolic dysfunction comprising an apolipoprotein peptide/phospholipid complex |
CA2807448A1 (en) | 2010-08-30 | 2012-03-08 | F. Hoffmann-La Roche Ag | Tetranectin-apolipoprotein a-i, lipid particles containing it and its use |
CA2807441A1 (en) | 2010-08-30 | 2012-03-08 | F. Hoffmann-La Roche Ag | Method for producing a lipid particle, the lipid particle itself and its use |
BR112013004397A2 (en) | 2010-08-30 | 2017-06-27 | Hoffmann La Roche | method for producing a lipid particle, the lipid particle itself and its use |
ES2388273B1 (en) * | 2011-03-16 | 2013-10-01 | Consejo Superior De Investigaciones Científicas (Csic) | USE OF S1P RECEPTOR INHIBITORS FOR THE TREATMENT OF CALCIFIED AORTIC STENOSIS |
CA2838070A1 (en) | 2011-08-25 | 2013-02-28 | F. Hoffmann-La Roche Ag | Shortened tetranectin-apolipoprotein a-i fusion protein, a lipid particle containing it, and uses thereof |
SG11201609084QA (en) | 2014-05-02 | 2016-11-29 | Cerenis Therapeutics Holding Sa | Hdl therapy markers |
ES2952838T3 (en) * | 2016-12-15 | 2023-11-06 | Nestle Sa | Compositions and methods that modulate cholesterol in a pet |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090186808A1 (en) * | 2006-06-01 | 2009-07-23 | Jean-Claude Tardif | Method and Compound for the Treatment of Valvular Disease |
US8163699B2 (en) | 2006-06-01 | 2012-04-24 | Montreal Heart Institute | Method for the treatment of valvular disease |
US20100267631A1 (en) * | 2009-02-16 | 2010-10-21 | Jean-Louis Dasseux | Apolipoprotein a-i mimics |
US8378068B2 (en) | 2009-02-16 | 2013-02-19 | Cerenis Therapeutics Holding Sa | Apolipoprotein A-I mimics |
US8993597B2 (en) | 2009-02-16 | 2015-03-31 | Cerenis Therapeutics Holding Sa | Apolipoprotein A-I mimics |
US9388232B2 (en) | 2009-02-16 | 2016-07-12 | Cerenis Therapeutics Holding Sa | Apolipoprotein A-I mimics |
US9981008B2 (en) | 2009-02-16 | 2018-05-29 | Cerenis Therapeutics Holding Sa | Apolipoprotein A-I mimics |
Also Published As
Publication number | Publication date |
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WO2007137400A1 (en) | 2007-12-06 |
ES2402823T3 (en) | 2013-05-09 |
JP2014037408A (en) | 2014-02-27 |
JP2009538835A (en) | 2009-11-12 |
MX2008015337A (en) | 2009-11-26 |
CN101489577A (en) | 2009-07-22 |
JP5394236B2 (en) | 2014-01-22 |
CA2653840A1 (en) | 2007-12-06 |
EP2537526A1 (en) | 2012-12-26 |
HK1129585A1 (en) | 2009-12-04 |
US20090186808A1 (en) | 2009-07-23 |
EP2026829A1 (en) | 2009-02-25 |
US8163699B2 (en) | 2012-04-24 |
CN101489577B (en) | 2013-10-16 |
EP2026829A4 (en) | 2010-02-24 |
EP2026829B1 (en) | 2013-01-09 |
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