METHODS AND COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF PULMONARY ARTERIAL HYPERTENSION
The disclosure provides methods of preventing or treating pulmonary arterial hypertension (PAH) in a mammalian subject, reducing risk factors associated with PAH, and/or reducing the likelihood or severity of PAH. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide.
1 . A method for treating or preventing pulmonary arterial hypertension (PAH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof, thereby resulting in the treatment or prevention of one or more signs or symptoms of PAH.
2 . The method of claim 1 , wherein the subject displays elevated blood levels of brain natriuretic peptide (BNP) and/or N-terminal fragment of proBNP (NT-proBNP) compared to a normal control subject, and wherein peptide administration normalizes blood levels of BNP and/or NT-proBNP.
3 . The method of any one of claim 1 or 2 , wherein the subject has been diagnosed as having PAH.
4 . The method of claim 3 , wherein the signs or symptoms of PAH comprise one or more of persistent dyspnea on exertion, chest pain, light-headedness, exertional presyncope/syncope, palpitations, fatigue, weakness, hoarseness in the voice due to compression of the left laryngeal nerve by the dilated pulmonary artery, venous jugular distension, hepato jugular reflux, hepatomegaly, hepatalgia, lower limb edema, ascites, generalized edema, intimal fibrosis of pulmonary arteries, increased medial thickness of pulmonary arteries, intimal hyperplasia of muscular pulmonary arteries, pulmonary artery thrombotic lesions, pulmonary arteriolar occlusion, pulmonary vascular pruning, plexiform lesions in pulmonary arteries, elevated serum or plasma brain natriuretic peptide (BNP) (>180 pg/mL), and elevated serum or plasma N-terminal fragment of proBNP (NT-proBNP) (≥1400 pg/mL).
5 . The method of any one of claims 1 - 4 , wherein the subject is human.
6 . The method of any one of claims 1 - 5 , wherein the peptide is administered orally, topically, systemically, intravenously, subcutaneously, transdermally, iontophoretically, intranasally, intraperitoneally, intramuscularly, or by pulmonary inhalation.
7 . The method of any one of claims 1 - 6 , further comprising separately, sequentially or simultaneously administering an additional therapeutic agent to the subject.
8 . The method of claim 7 , wherein the additional therapeutic agent is selected from the group consisting of: endothelin receptor antagonists (ETRAs), guanylate cyclase stimulators, prostacyclin analogues, phosphodiesterase (PDE)-5 inhibitors, dehydroepiandrosterone (DHEA), cyclosporine, tacrolimums, bestatin, imatinib, calcium-channel blockers (CCBs), dichloroacetate (DCA), trimetazidine, ranolazine, 4-phenylbutyrate, tauroursodeoxycholic acid, and salubrinal.
9 . The method of claim 8 , wherein the combination of the peptide and the additional therapeutic agent has a synergistic effect in the prevention or treatment of PAH.
10 . A method for reducing the risk of PAH in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of the peptide D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 or a pharmaceutically acceptable salt thereof, thereby resulting in the prevention or delay of onset of one or more signs or symptoms of PAH.
11 . The method of claim 10 , wherein the subject harbors a mutation in the bone morphogenetic protein receptor 2 (BMPR 2 ) gene.
12 . The method of any one of claims 10 - 11 , wherein the subject is human.
13 . The method of any one of claims 10 - 12 , wherein the peptide is administered orally, topically, systemically, intravenously, subcutaneously, transdermally, iontophoretically, intranasally, intraperitoneally, intramuscularly, or by pulmonary inhalation.
14 . The method of any one of claims 10 - 13 , further comprising separately, sequentially, or simultaneously administering the additional therapeutic agent to the subject.
15 . The method of claim 14 , wherein the additional therapeutic agent is selected from the group consisting of: endothelin receptor antagonists (ETRAs), guanylate cyclase stimulators, prostacyclin analogues, phosphodiesterase (PDE)-5 inhibitors, dehydroepiandrosterone (DHEA), cyclosporine, tacrolimums, bestatin, imatinib, calcium-channel blockers (CCBs), dichloroacetate (DCA), trimetazidine, ranolazine, 4-phenylbutyrate, tauroursodeoxycholic acid, and salubrinal.
16 . The method of claim 15 , wherein the combination of the peptide and the additional therapeutic agent has a synergistic effect in reducing the risk of PAH.