Methods and compositions for the treatment of peripheral artery disease

Abstract

Compositions and methods for treating peripheral artery disease in a patient are provided. Compositions comprise recombinant fibroblast growth factor-2. Fibroblast growth factor, such as FGF-2, is administered in therapeutically effective amounts to treat or prevent peripheral artery disease including claudication and critical limb ischemia. Pharmaceutical compositions comprising a therapeutically effective amount of FGF-2 and a pharmaceutically acceptable carrier are also provided. The methods of the invention to treat peripheral artery disease and claudication comprise administering at least a single dose of a pharmaceutical composition comprising the FGF, such as FGF-2, via intra-arterial, intravenous, or intramuscular infusion to the patient. It is recognized that increased benefits may result from multiple dosing, including intermittent dosing.

That which is claimed:  
     
         1 . A method for treating peripheral artery disease in a patient, said method comprising administering to said patient a therapeutically effective amount of fibroblast growth factor (FGF), wherein said therapeutically effective amount of FGF is divided into two doses and a single dose is administered into each leg of said patient within a one hour period.  
     
     
         2 . The method of  claim 1 , wherein said FGF is administered by intra-arterial infusion (IA) into at least one artery of each leg of said patient.  
     
     
         3 . The method of  claim 2 , wherein said FGF is administered into the common femoral artery of each leg of said patient.  
     
     
         4 . The method of  claim 3 , wherein said FGF is administered via bilateral delivery using a catheter.  
     
     
         5 . The method of  claim 3 , wherein said FGF is administered via direct IA infusion into the common femoral artery of each leg of said patient.  
     
     
         6 . The method of  claim 1 , wherein said FGF is administered by one or more intramuscular (IM) injections.  
     
     
         7 . The method according to  claim 1 , wherein said peripheral artery disease is evidenced by claudication.  
     
     
         8 . The method according to  claim 7 , wherein said patient has critical limb ischemia.  
     
     
         9 . The method of  claim 1 , wherein said FGF is FGF-2.  
     
     
         10 . The method of  claim 9 , wherein said FGF-2 is a recombinant molecule.  
     
     
         11 . The method of  claim 10 , wherein said FGF-2 comprises the sequence set forth in FIG. 2 (SEQ ID NO:2), FIG. 3 (SEQ ID NO:4), FIG. 4 (SEQ ID NO:6), FIG. 5 (SEQ ID NO:8) or an angiogenically active fragment or mutein thereof.  
     
     
         12 . The method of  claim 11 , wherein said mutein comprises an FGF-2 molecule wherein at least one constituent cysteine residue is replaced by a neutral amino acid.  
     
     
         13 . The method of  claim 12 , wherein the neutral amino acid is serine or threonine.  
     
     
         14 . The method of  claim 11 , wherein said FGF-2 is administered simultaneously with another molecule selected from the group consisting of heparin and other proteoglycan.  
     
     
         15 . The method of  claim 14 , wherein said heparin is a low molecular weight molecule.  
     
     
         16 . The method of  claim 14 , wherein said heparin is unfractionated heparin.  
     
     
         17 . The method of  claim 11 , wherein said FGF-2 is administered within about 5 minutes to about 60 minutes of heparin or proteoglycan administration to said patient.  
     
     
         18 . The method of  claim 17 , wherein said FGF-2 is administered within about 20 minutes to about 30 minutes of heparin or other proteoglycan administration to said patient.  
     
     
         19 . The method of  claim 11 , wherein said FGF-2 is administered in the absence of administering a molecule selected from the group consisting of heparin and other proteoglycan.  
     
     
         20 . The method of  claim 11 , wherein said therapeutically effective amount of FGF-2 is administered to said patient once in a 24 hour period.  
     
     
         21 . The method of  claim 11 , wherein said therapeutically effective amount of FGF-2 is administered to said patient once a week.  
     
     
         22 . The method of  claim 11 , wherein said therapeutically effective amount of FGF-2 is administered to said patient once a month, once every 2 months, once every 3 months, once every four months, once every five months, or once every six months.  
     
     
         23 . The method of  claim 11 , wherein said therapeutically effective amount of FGF-2 is administered as an adjunct to vascular surgery, mechanical bypass surgery, angioplasty, or angiogram.  
     
     
         24 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 0. 1 μg/kg to about 1 μg/kg.  
     
     
         25 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 1 μg/kg to about 3 μg/kg.  
     
     
         26 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 3 μg/kg to about 5 μg/kg.  
     
     
         27 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 5 μg/kg to about 7 μg/kg.  
     
     
         28 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 7 μg/kg to about 9 μg/kg.  
     
     
         29 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 9 μg/kg to about 10 μg/kg.  
     
     
         30 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 10 μg/kg to about 15 μg/kg.  
     
     
         31 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 15 μg/kg to about 20 μg/kg.  
     
     
         32 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 20 μg/kg to about 25 μg/kg.  
     
     
         33 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 25 μg/kg to about 30 μg/kg.  
     
     
         34 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 30 μg/kg to about 40 μg/kg.  
     
     
         35 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 40 μg/kg to about 50 μg/kg.  
     
     
         36 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 4 μg to about 0.3 mg.  
     
     
         37 . The method of  claim 11 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 0.3 mg to about 3.5 mg.  
     
     
         38 . The method of  claim 37 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 1.0 to about 2.0mg.  
     
     
         39 . The method of  claim 37 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 2.0 to about 3.5mg.  
     
     
         40 . The method of  claim 9 , wherein said FGF-2 is administered to said patient by intra-arterial (IA) or intravenous (IV) infusion.  
     
     
         41 . The method of  claim 9 , wherein said FGF-2 is administered to said patient by one or more intramuscular (IM) injections.  
     
     
         42 . The method of  claim 9 , wherein said FGF-2 is administered to said patient by subcutaneous (SC) injection.  
     
     
         43 . The method of  claim 9 , wherein said administering of FGF-2 provides an improvement in peak walking time (PWT) in said patient relative to PWT in the absence of said administering of FGF-2.  
     
     
         44 . The method of  claim 9 , wherein said administering of FGF-2 provides an improvement in anklebrachial index (ABI) in said patient relative to ABI in the absence of said administering of FGF-2.  
     
     
         45 . The method of  claim 9 , wherein said administering of FGF-2 results in a reduction in body pain.  
     
     
         46 . The method of  claim 9 , wherein said administering of FGF-2 improves stair climbing ability.  
     
     
         47 . The method of  claim 9 , wherein said administering of FGF-2 reduces the severity of claudication.  
     
     
         48 . A method for treating peripheral artery disease in a patient, said method comprising administering to said patient a therapeutically effective amount of fibroblast growth factor-2 (FGF-2), wherein said therapeutically effective amount is about 0.1 μg/kg to about 9.9 μμg/kg.  
     
     
         49 . The method of  claim 48 , wherein said therapeutically effective amount of FGF-2 is administered as part of a pharmaceutical composition.  
     
     
         50 . The method of  claim 49 , wherein said pharmaceutical composition is a stabilized FGF-2-DTT formulation.  
     
     
         51 . The method of  claim 48 , wherein said FGF-2 is administered simultaneously with another molecule selected from the group consisting of heparin and other proteoglycan.  
     
     
         52 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 0.1 μg/kg to about 1 μg/kg.  
     
     
         53 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 1 μg/kg to about 3 μg/kg.  
     
     
         54 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 3 μg/kg to about 5 μg/kg.  
     
     
         55 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 5 μg/kg to about 7 μg/kg.  
     
     
         56 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 7 μg/kg to about 8 μg/kg.  
     
     
         57 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 8 μg/kg to about 9 μg/kg.  
     
     
         58 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 9 μg/kg to about 9.9 μg/kg.  
     
     
         59 . The method of  claim 48 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 7.0 μg to about 0.7 mg.  
     
     
         60 . The method of  claim 59 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 9.0 μg to about 0.5 mg.  
     
     
         61 . The method of  claim 60 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 0.1 mg to about 0.4 mg.  
     
     
         62 . The method of  claim 61 , wherein said therapeutically effective amount of said FGF-2 or said angiogenically active fragment or mutein thereof is about 0.1 mg to about 0.2 mg.  
     
     
         63 . The method of  claim 48 , wherein said FGF-2 is administered to said patient by intra-arterial (IA) or intravenous (IV) infusion.  
     
     
         64 . The method of  claim 48 , wherein said FGF-2 is administered to said patient by one or more intramuscular (IM) injections.  
     
     
         65 . A method for improving peak walking time in a patient with intermittent claudication, said method comprising administering to said patient a therapeutically effective amount of fibroblast growth factor (FGF), wherein said therapeutically effective amount of FGF is divided into two doses and a single dose is administered into each leg of said patient within a one hour period.  
     
     
         66 . The method of  claim 65 , wherein said FGF is FGF-2.  
     
     
         67 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 0.1 μg/kg to about 1 μg/kg.  
     
     
         68 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 1 μg/kg to about 3 μg/kg.  
     
     
         69 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 3 μg/kg to about 5 μg/kg.  
     
     
         70 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 5 μg/kg to about 9 μg/kg.  
     
     
         71 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 9 μg/kg to about 10 μg/kg.  
     
     
         72 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 10 μg/kg to about 20 μg/kg.  
     
     
         73 . The method of  claim 66 , wherein said therapeutically effective amount of said FGF-2 is about 20 μg/kg to about 30 μg/kg.  
     
     
         74 . A method for improving ankle-brachial index in a patient with intermittent claudication, said method comprising administering to said patient a therapeutically effective amount of fibroblast growth factor (FGF), wherein said therapeutically effective amount of FGF is divided into two doses and a single dose is administered into each leg of said patient within a one hour period.  
     
     
         75 . The method of  claim 74 , wherein said FGF is FGF-2.  
     
     
         76 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 0.1 μg/kg to about 1 μg/kg.  
     
     
         77 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 1 μg/kg to about 3 μg/kg.  
     
     
         78 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 3 μg/kg to about 5 μg/kg.  
     
     
         79 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 5 μg/kg to about 9 μg/kg.  
     
     
         80 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 9 μg/kg to about 10 μg/kg.  
     
     
         81 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 10 μg/kg to about 20 μg/kg.  
     
     
         82 . The method of  claim 75 , wherein said therapeutically effective amount of said FGF-2 is about 20 μg/kg to about 30 μg/kg.