Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-01-16
2001-10-23
Clark, Deborah J. R. (Department: 1633)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S235100, C424S093200
Reexamination Certificate
active
06306830
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for enhancing cardiac function in mammalian hearts, more specifically, the invention relates to techniques and polynucleotide constructs for enhancing myocardial &bgr;-adrenergic responsiveness using in vivo gene therapy.
BACKGROUND
It has been reported that 3-4 million adults in the United States have congestive heart failure (abbreviated “CHF” herein); and the incidence of CHF is increasing (see, e.g., Baughman, K., Cardiology Clinics 13: 27-34, 1995). Annually in US hospitals, CHF is the most frequent non-elective admission and the discharge diagnosis for 500,000 patients. Once symptoms of heart failure are moderately severe, the prognosis is worse than most cancers in that 50% of such patients are dead within 2 years (Braunwald, E. (ed), In: Heart Disease, W. B. Saunders, Philadelphia, page 471-485, 1988). Although medical therapy can initially attenuate the symptoms of heart failure (edema, breathlessness, fluid in the lungs), and in some cases prolong life, the prognosis in this disease, even with medical treatment, is grim (see, e.g., Baughman, K., Cardiology Clinics 13: 27-34, 1995).
CHF is defined as abnormal heart function resulting in inadequate cardiac output for metabolic needs (Braunwald, E. led), In: Heart Disease, W. B. Saunders, Philadelphia, page 426, 1988). Symptoms include breathlessness, fatigue, weakness, leg swelling, and exercise intolerance. On physical examination, patients with heart failure tend to have elevations in heart and respiratory rates, rales (an indication of fluid in the lungs), edema, jugular venous distension, and, in general, enlarged hearts. The most common cause of CHF is atherosclerosis which causes blockages in the blood vessels (coronary arteries) that provide blood flow to the heart muscle. Ultimately such blockages may cause myocardial infarction (death of heart muscle) with subsequent decline in heart function and resultant heart failure. Other causes of CHF include valvular heart disease, hypertension, viral infections of the heart, alcohol, and diabetes. Some cases of heart failure occur without clear etiology and are called idiopathic.
CHF is also typically accompanied by alterations in one or more aspects of &bgr;-adrenergic neurohumoral function; see, e.g., Bristow M R, et al., N Engl J Med 307:205-211, 1982; Bristow M R, et al., Circ Res 59:297-309, 1986; Ungerer M, et al., Circulation 87: 454-461, 1993; Feldman A M, et al., J Clin Invest 82:189-197, 1988; Bristow M R, et al., J Clin Invest 92: 2737-2745, 1993; Calderone A, et al., Circ Res 69:332-343. 1991; Marzo K P, et al., Circ Res 69:1546-1556, 1991; Liang C-S, et al., J Clin Invest 84: 1267-1275, 1989; Roth D A, et al., J Clin Invest 91: 939-949, 1993; Hadcock J R and Malbon C C: Proc NatI Acad Sci 85:5021-5025, 1988; Hadcock J R, et al., J Biol Chem 264: 19928-19933, 1989; Mahan, et al., Proc Natl Acad Sci USA 82:129-133, 1985; Hammond H K, et al., Circulation 85:269-280, 1992; Neumann J, et al., Lancet 2: 936-937, 1988; Urasawa K, et al., In: G Proteins: Signal Transduction and Disease, Academic Press, London. 44-85, 1992; Bohm M, Mol Cell Biochem, 147: 147-160, 1995; Eschenhage T, et al., Z Kardiol, 81 (Suppl 4): 33-40, 1992; and Yamamoto J, et al., J Mol Cell, 26: 617-626, 1994. See also the numerous additional references regarding various adenylylcyclase enzymes by, e.g., Fujita M et al., Circulation, 90: (No. 4 Part 2), 1994; Yoshimura M et al., Proc NatI Acad Sci USA, 89:6716-6720, 1992; Krupinski J et al., J Biol Chem, 267:24858-24862, 1992; Ishikawa Y et al., J Biol Chem, 267:13553-13557, 1992; Ishikawa Y et al., J. Clin Invest, 93:2224-2229, 1994; Katsushika S et al., Proc Natl Acad Sci USA, 89:8774-8778, 1992; Wallach J et al., FEBS Lett, 338:257-263, 1994; Watson P A et al., J Biol Chem, 269:28893-28898, 1994; Manolopoulos V G et al., Biochem Biophys Res Commun, 208:323-331, 1995; Yu H J et al., FEBS Lett, 374:89-94, 1995; and Chen Z et al., J Biol Chem, 270:27525-27530, 1995.
As a result of these studies and others, efforts to treat CHF have focused on the administration of pharmacological agents, such as catecholamines and other &bgr;-adrenergic agonists, as means of stimulating &bgr;-adrenergic responses in dysfunctional hearts. Such therapeutic approaches have been only partly successful. Furthermore, long-term exposure to catecholamines can be detrimental. In particular, the heart tends to become less responsive to &bgr;-adrenergic stimulation, and such unresponsiveness is typically associated with high levels of catecholamines in plasma, a factor generally linked to a poor prognosis.
Present treatments for CHF include pharmacological therapies, coronary revascularization procedures (e.g. coronary artery bypass surgery and angioplasty), and heart transplantation. Pharmacological therapies have been directed toward increasing the force of contraction of the heart (by using inotropic agents such as digitalis and &bgr;-adrenergic receptor agonists), reducing fluid accumulation in the lungs and elsewhere (by using diuretics), and reducing the work of the heart (by using agents that decrease systemic vascular resistance such as angiotensin converting enzyme inhibitors). &bgr;-adrenergic receptor antagonists have also been tested. While such pharmacological agents can improve symptoms, and potentially prolong life, the prognosis in most cases remains dismal.
Some patients with heart failure due to associated coronary artery disease can benefit, at least temporarily, by revascularization procedures such as coronary artery bypass surgery and angioplasty. Such procedures are of potential benefit when the heart muscle is not dead but may be dysfunctional because of inadequate blood flow. If normal coronary blood flow is restored, viable dysfunctional myocardium may contract more normally, and heart function may improve. However, revascularization rarely restores cardiac function to normal or near-normal levels in patients with CHF, even though mild improvements are sometimes noted.
Finally, heart transplantation can be a suitable option for patients who have no other confounding diseases and are relatively young, but this is an option for only a small number of patients with heart failure, and only at great expense. In summary, CHF has a very poor prognosis and responds poorly to current therapies.
Further complicating the physiological conditions associated with CHF, are various natural adaptations that tend to occur in patients with dysfunctional hearts. Although these natural responses can initially improve heart function, they ultimately result in problems that can exacerbate CHF, confound treatment, and have adverse effects on survival. There are three such adaptive responses commonly observed in CHF: (i) volume retention induced by changes in sodium reabsorption, which expands plasma volume and initially improves cardiac output; (ii) cardiac enlargement (from dilation and hypertrophy) which can increase stroke volume while maintaining relatively normal wall tension; and (iii) increased norepinephrine release from adrenergic nerve terminals impinging on the heart which, by interacting with cardiac &bgr;-adrenergic receptors, tends to increase heart rate and force of contraction, thereby increasing cardiac output. However, each of these three natural adaptations tends ultimately to fail for various reasons. In particular, fluid retention tends to result in edema and retained fluid in the lungs that impairs breathing; heart enlargement can lead to deleterious left ventricular remodeling with subsequent severe dilation and increased wall tension, thus exacerbating CHF; and long-term exposure of the heart to norepinephrine tends to make the heart unresponsive to adrenergic stimulation and is linked with poor prognosis.
Controlled use of pharmacological agents, such as &bgr;-adrenergic agonists; and other modulatory drugs, thus remains one of the major forms of treatment despite its shortfalls, including its potentially adverse effect on survival. Researchers who have analyzed a
Gao Meihua
Hammond H. Kirk
Insel Paul A.
Ping Peipei
Post Steven R.
Clark Deborah J. R.
Morrison & Foerster / LLP
The Regents of the University of California
Wilson Michael C.
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