METHODS AND COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF DISEASE
The present technology is directed to compositions and methods for preventing, ameliorating, or reducing the severity of one or more signs, or symptoms associated with a reduction of function, decreased expression level of, and/or deficiency in one or more of COL4A3, COL4A4 and COL4A5 genes. Also disclosed herein are methods of preventing or treating Alport Syndrome in a mammalian subject, reducing risk factors associated with Alport Syndrome, and/or reducing the likelihood or severity of Alport Syndrome. The methods comprise administering to the subject an effective amount of an aromatic-cationic peptide.
1 - 37 . (canceled)
38 . A method for reducing progressive glomerulonephritis characterized by mesangial matrix expression and GBM irregularities in a mammalian subject having or suspected of having Alport Syndrome, 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.
39 . The method of claim 38 , wherein the subject has decreased expression of in one or more of COL4A3, COL4A4, or COL4A5 as compared to a normal control subject.
40 . The method of claim 38 , wherein the mammalian subject has increased expression of MMP-9 in mesangial cells compared to a normal control subject.
41 . The method of claim 38 , wherein the mammalian subject has altered urine levels of one or more of ADAM8, fibronectin, myosin 10, MMP-2, and podocin as compared to a normal control subject.
42 . The method of claim 38 , wherein a combination of three urine biomarkers is altered in the mammalian subject as compared to a normal control subject.
43 . The method of claim 42 , wherein the mammalian subject has altered urine levels of fibronectin, myosin 10 and MMP-2 as compared to a normal control subject.
44 . The method of claim 42 , wherein the mammalian subject has altered urine levels of fibronectin, myosin 10 and MMP-9 as compared to a normal control subject.
45 . The method of claim 38 , wherein a combination of two urine biomarkers is altered in the mammalian subject as compared to a normal control subject.
46 . The method of claim 45 , wherein the mammalian subject has altered urine levels of myosin 10 and MMP-2 as compared to a normal control subject.
47 . The method of claim 45 , wherein the mammalian subject has altered urine levels of myosin 10 and MMP-9 as compared to a normal control subject.
48 . The method of claim 38 , wherein administration of the peptide results in elevated Mfn1 expression and/or function as compared to an untreated subject.
49 . The method of claim 38 , wherein the peptide is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, iontophoretically, transmucosally, or intramuscularly.
50 . The method of claim 38 , further comprising separately, sequentially or simultaneously administering one or more of: angiotensin II converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARBs), HMG-COA reductase inhibitors, aldosterone inhibitors and the matrix metalloproteinase inhibitor BAY-12-9566.
51 . The method of claim 38 , wherein the subject is human.
52 . The method of claim 38 , wherein the pharmaceutically acceptable salt comprises acetate, tartrate or trifluoroacetate.