Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-07-17
2004-04-13
Wehbé, Anne M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S325000, C435S455000, C435S456000, C536S023200, C424S093200
Reexamination Certificate
active
06720309
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERAL SPONSORED RESEARCH AND DEVELOPMENT
Part of the work performed during development of this invention was supported by U.S. Government funds. The U.S. Government may have certain rights in this invention.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a gene therapy method for inducing pulmonary vasodilation by transducing a nitric oxide synthase gene into lung tissue. This invention also relates to methods of treating pulmonary hypertension and pharmaceutical compositions for treating pulmonary hypertension.
2. Related Art
Blood flow through the pulmonary circulation is highly regulated. For example, the pulmonary endothelium regulates pulmonary blood flow and maintains a low vascular resistance by releasing vasoactive substances, which control vasomotor tone, vascular patency, and normal vessel wall architecture. Vanhoutte,
N. Engl. J. Med
. 319:512-513 (1988).
1
Vasomotor tone relates to the degree of active tension in the vessel wall and partially determines the luminal diameter of the vessel. Vascular patency refers to the condition of a blood vessel where the internal luminal diameter is normal and blood flow is unimpeded.
1
This article and all other articles, patents, or other documents cited or referred to in this application are specifically incorporated herein by reference.
Nitric oxide is one compound that plays an important role in regulating pulmonary blood flow. However, it is a gas with no known storage mechanism, which diffuses freely across membranes and is extremely labile. Nitric oxide has a biological half-life on the order of seconds, and its production is tightly regulated.
Nitric oxide is produced by two classes of nitric oxide synthases (NOS). Nathan,
FASEB J
. 6:3051-3064 (1992). The constitutively expressed nitric oxide synthases, exist as two isoforms: the endothelial nitric oxide synthase (ceNOS) and the neuronal nitric oxide synthase, (nNOS). These isoforms are expressed in vascular endothelial cells, platelets, and in neural tissues such as the brain. This class of nitric oxide synthase is calcium and calmodulin dependent. In blood vessels ceNOS mediates endothelium dependent vasodilation in response to acetylcholine, bradykinin, and other mediators. Nitric oxide levels increase in response to shear stress, i.e., forces on the blood vessels in the direction of blood flow, and the mediators of inflammation. Furchgott and Vanhoutte,
FASEB J
. 3:2007-2018 (1989); Ignarro,
FASEB J
. 3:31-36 (1989).
In the nervous system, the neuronal NOS isoform is localized to discrete populations of neurons in the cerebellum, olfactory bulb, hippocampus, corpus striatum, basal forebrain, and brain stem. Bredt et al.,
Nature
347:768-770 (1990). Neuronal NOS is also concentrated in the posterior pituitary gland, in the superoptic and paraventricular hypothalmic nuclei, and in discrete ganglion cells of the adrenal medulla Id. The widespread cellular localization of the neuronal NOS isoform and the short half-life and diffusion properties of nitric oxide suggest that NOS plays a role in nervous system morphogenesis and synaptic plasticity.
The second class, inducible nitric oxide synthase (iNOS), is expressed in macrophages, hepatocytes, and tumor cells. Steuhr et al.,
Adv. Enzymol. Relat. Areas Mol. Biol
. 65:287-346 (1992); Lowenstein et al.,
Proc. Natl. Acad. Sci
. (
USA
) 89:6711-6715 (1992). The inducible form of NOS is not calcium regulated, but its expression is induced by cytokines. This form of NOS functions as a cytotoxic agent, and NO produced by inducible NOS targets tumor cells and pathogens. Hibbs et al.,
Biochem. Biophys. Res. Comm
. 157:87-94 (1988); Nathan,
FASEB J
. 6:3051-3064 (1992); Marletta,
Trends Biochem. Sci
. 14:488-492 (1989).
All isoforms of NOS catalyze the conversion of L-arginine to L-citrulline with production of NO. In vascular smooth muscle cells and in platelets, NO activates soluble guanylate cyclase, which increases intracellular guanosine 3′,5′-cyclic monophosphate (cGMP), thereby inducing vasorelaxation and inhibiting platelet aggregation. The anti-platelet effect of NO and its vasodilatory and anti-proliferative action on pulmonary vascular smooth muscle cells suggest that NO may be an important modulator of pulmonary hypertension. Moncada et al.,
Pharmacol. Res
. 43:109-142 (1991); Garg et al.,
J. Clin. Invest
. 83:1774-1777 (1989); Roberts et al.,
Circ. Res
. 76:215-222 (1995); Heath,
Eur. Respir. Rev
. 3:555-558 (1993); Radomski et al.,
Biochem. Biophys. Res. Commum
. 148:1482-1489 (1987); Assender et al.,
J. Cardiovasc. Pharmacol
. 17:104-107 (1991); de Graaf et al.,
Circulation
85:2284-2290 (1992).
The sequence of the various NOS isoforms have been published or are available in Genbank under the following accession numbers:
Species:
Gene:
Man
Rat
Mouse
Cow
Neuronal
U17327
X59949
D14552
D16408
L02881
Macrophage (iNOS)
L09210
D14051
M87039
U18331
X85759-81
D83661
U43428
U14640
U18334
U26686
L23806
U31511
U16359
L09126
U20141
D44591
M92649
U05810
X76881
M84373
X73029
U02534
L24553
L12562
Endothelial
X76303-16
U18336
M89952
L26914
U28933
L27056
L23210
M95674
L10693
M99057
M95296
M89952
M93718
Each of these sequences are expressly incorporated herein by reference. The different forms of NOS are about 50 to 60 percent homologous overall.
Several in vitro and in vivo results suggest that NO may play a role in the pulmonary vascular response to hypoxia. For example, in perfused isolated lungs, hypoxia induces a significant reduction in contractile responses to acetylcholine and to inhibitors of NOS. Adnot et al.,
J. Clin. Invest
. 87:155-162 (1991). In isolated pulmonary vascular rings hypoxia suppresses basal and agonist-stimulated release of NO. Johns et al.,
Circ. Res
. 65:1508-1515 (1989); Shaul et al.,
J. Cardiovasc. Pharmacol
. 22:819-827 (1993). In endothelial cells, hypoxia inhibits NO production by reducing ceNOS mRNA levels and ceNOS mRNA stability. McQuillan et al.,
Am J. Physiol
. 267:H1921-H1927 (1994). Moreover, downregulation of ceNOS mRNA and protein correlate inversely with the severity of the plexogenic pulmonary arteriopathy in the lungs of patients with pulmonary hypertension. Giaid et al.,
N. Engl. J. Med
. 333:214-221 (1995). Therefore, hypoxia-induced hypertension may correlate with reduced NO generation from pulmonary endothelium affecting the balance between pulmonary vasoconstrictive and vasodilatory stimuli.
In addition to hypoxia-induced pulmonary hypertension, there are other forms of pulmonary hypertension. For example, pulmonary hypertension can result from disease states such as interstitial lung diseases with fibrosis, e.g., sarcoidosis and pneumoconioses, e.g., silicosis. Pulmonary hypertension on can also result from emboli, from parasitic diseases such as schistosomiasis or filariosis, from multiple pulmonary artery thromboses associated with sickle cell disease, and from cardiac disease, such as cor pulmonale, and from ischemic and valvular heart disease.
In addition to resulting from other disease, pulmonary hypertension can also be a primary disease condition. Primary pulmonary hypertension is an uncommon disease, which can only be diagnosed after a thorough search for the usual causes of pulmonary hypertension. Ordinarily, the natural course of this disease encompasses about five years, and it is normally fatal, with treatment being palliative. While pharmacological vasodilator therapy for primary and secondary pulmonary hypertension is known, these methods often have undesirable systemic hypotensive side effects.
The use of gene therapy for the treatment of various diseases and disorders has advanced significantly over the last several years. In contrast to traditional pharmaceuticals, gene therapy refers to the transfer and insertion of new genetic information into cells or the substitution of deficient genetic information for the therapeutic treatment of diseases or disorders. In some cases the gene is expressed in the target cell, while in other cases expression is
Bloch Kenneth D.
Collen Desire
Janssens Stefan
Leuven Research and Development V.Z.W.
Wehbe Anne M.
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