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WO 2007/067570 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 14 June 2007 (14.06.2007) WO 2007/067570 Al (51) International Patent Classification: (74) Agent: DANEK, Shelley, C ; MARSHALL, GERSTEIN A61K 31/519 (2006.01) A61P 9/12 (2006.01) & BORUN LLP, 233 S. WACKER DRIVE, SUITE 6300, A61P 9/10 (2006.01) SEARS TOWER, Chicago, IL 60606-6357 (US). (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2006/046449 AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (22) International Filing Date: GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, 5 December 2006 (05.12.2006) JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, (25) Filing Language: English MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 60/742,578 5 December 2005 (05.12.2005) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 60/764,979 3 February 2006 (03.02.2006) US ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 60/817,847 30 June 2006 (30.06.2006) US European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (71) Applicant (for all designated States except US): RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, BIOMARIN PHARMACEUTICAL INC. [US/US]; GN, GQ, GW, ML, MR, NE, SN, TD, TG). 105 DIGITAL DRIVE, Novato, CA 94949 (US). Published: (72) Inventors; and — with international search report (75) Inventors/Applicants (for US only): OPPENHEIMER, — before the expiration of the time limit for amending the Daniel, I. [US/US] ;4516 HILLSBOROUGH DRIVE, Cas claims and to be republished in the event of receipt of tro Valley, CA 94546 (US). KAKKIS, Emil, D. [US/US]; amendments 2512 LAGUNA VISTA DRIVE, Novato, CA 94949 (US). For two-letter codes and other abbreviations, refer to the "G uid DORENBAUM, Alejandro [US/US]; 120 STANFORD ance Notes on Codes and Abbreviations" appearing at the beg in AVENUE, Mill Valley, CA 94941 (US). ning of each regular issue of the PCT Gazette. (54) Title: METHODS AND COMPOSITIONS FOR THE TREATMENT OF DISEASE (57) Abstract: The present invention is directed to a novel methods and compositions for the therapeutic intervention of vascular complications associated with diabetes, hyperlipidemias, and various cardiovascular disorders including but not limited to recalci- trant hypertension, coronary artery disease, pulmonary arterial hypertension, congestive heart failure, and hemolytic anemias. More specifically, the specification describes methods and compositions for treating such vascular disorders using compositions compris- ing BH4 and derivative thereof. Combination therapies of BH4 and other therapeutic regimens are contemplated. METHODS AND COMPOSITIONS FOR THE TREATMENT OF VASCULAR DISEASE This application claims priority of U.S. Provisional Application No. 60/742,578 filed December 5 2005; U.S. Provisional Application No. 60/764,979 filed February 3, 2006; and U.S. Provisional Application No. 60/8 17,847 filed June 30, 2006, each of which is hereby incorporated by reference in its entirety. BACKGROUND Field of the Invention The present invention is generally directed to the therapeutic intervention of vascular disease. More particularly, the present invention is directed to methods and compositions for the treatment of endothelial dysfunction associated with vascular dysfunction. Background of the Related Art Diabetes and its cardiovascular complications are the leading cause of mortality and morbidity in the United States and the western world. Several causative factors are implicated in the development of these diseases including hereditary predisposition to the disease, gender, lifestyle factors such as smoking and diet, age, insulin resistance, hypertension, and hyperlipidemia, including hypercholesterolemia. Treatment options for diabetes and related cardiovascular diseases include various therapeutic agents such as cholesterol lowering drugs (e.g. statins), vasoactiove agents (e.g.s. PPAR gamma ligands, β blockers), ACE inhibitors, Angiotensin II receptor blockers, calcium channel blockers, vitamins and antioxidants (e.g. niacin, ascorbic acid or vitamin C). The rationale for using statin drugs to lower plasma cholesterol fails to explain why coronary heart attacks generally occur in individuals with non-critical blockages and why blockages do not occur in capillaries or veins. When used, statin drugs reduce the risk of a recurrent coronary event, only by 30 to 40%. The rationale for vasoactive drugs is to reduce blood pressure by acting directly or indirectly on vascular and/or cardiac smooth muscle, thereby decreasing vascular resistance to flow. However, such drugs do not treat the initial cause of elevated pressure and abnormal flow, but seek to reduce the resulting effect of the disorder. Such drugs activate the sympathetic nervous system by way of a baroreceptor reflex to produce an increased heart rate and force of myocardial contraction, which are not beneficial or desirable effects. Vitamin E, vitamin C, probucol and β-carotene constitute most of antioxidants currently applied for treatment of diabetes. Unfortunately, however, none of these agents when administered alone or in combination with other agents can adequately address cellular (i.e., skin or endothelial) dysfunction and other oxidative stress-mediated pathologies. Because of their 'mode' of action, tissue uptake and other relevant characteristics, all currently available antioxidants can only indirectly affect endothelium derived relaxing factor metabolism and action act only on certain reactive oxygen species (ROS). Further, they may adversely affect the course of the disease if incorrectly dosed. Moreover, present treatments for such disorders are short-term and have serious shortcomings with respect to long-term effectiveness. The use of therapeutic drugs for diabetes and the related acute and chronic occlusive vascular diseases of the heart central and peripheral vascular systems have to date been ineffective for favorable long-term results and do not treat the underlying pathophysiology or restore the structure and function of the blood vessels to normal states. Each of the therapeutic agents while having some beneficial effects on the patient have serious side effects and often need to be taken in high non- physiological doses. The side effects are often dose related. The adverse effects for the classes of therapeutic agents above include hypoglycemia, renal dysfunction, and myopathy including rhadomyolysis, hepatotoxicity, airway resistance and teratogenic effects if taken by pregnant subjects. Other side effects for such drugs include headache, heart palpitations, anxiety, mild depression, myocardial infarction,. congestive heart failure, fatigue and weakness. Further, a pharmacological dose may not be specific in its effect on the initial molecular cause of the disease activity, and treats a limited spectrum of effects in the diseases, which are dependent on several factors. In some cases, the adverse effects may be as simple as flushing and dyspepsia but result in a serious lack of patient compliance with the treatment regimen. To offset the adverse effects of the drugs, various combination therapies have been suggested as treatment options. Thus, there remains a need for a consistently effective and specific agent for the management of endothelial dysfunction underlying vascular disease without causing severe adverse side effects. The present invention is directed to addressing such a need. SUMMARY In general, the invention describes a therapeutic intervention of endothelial dysfunction resulting in vascular disease. The invention contemplates methods and compositions for treating a subject having a disease or disorder characterized by endothelial dysfunction, comprising administering to said subject a composition comprising tetrahydrobiopterin (BH4) or a precursor or derivative thereof, alone or in combination with a therapeutic agent, wherein said administration is effective in alleviating endothelial dysfunction of said subject as compared to said endothelial dysfunction in the absence of said BH4-containing composition. The invention further contemplates a method of treating a subject with endothelial dysfunction comprising administering a factor or combination of factors that enhances the production of the vasodilator nitric oxide (NO) alone or in combination with a therapeutic agent. In one aspect, the invention provides a method for treating a subject diagnosed as having diabetes-related vascular complications comprising administering BH4 or a precursor or derivative thereof, alone or in combination with another agent, wherein such agent is a therapeutic agent or a factor that enhances the production of the vasodilator nitric oxide (NO). In one embodiment, diabetes-related vascular complications include but are not limited to disorders of general vascular functions such as abnormal vascular compliance, endothelial dysfunction and hypertension;
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