Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-10-21
2001-01-23
McKelvey, Terry (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S021800, C514S04400A
Reexamination Certificate
active
06177403
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is gene therapy.
BACKGROUND OF THE INVENTION
It is well known that viruses naturally deliver nucleic acids to cells and have therefore been exploited as gene delivery vehicles. However, in order for a recombinant virus to delivery a nucleic acid to a cell, the virus must first have access to the cell. Circulating virus in a mammal may not have ready access to cells to which it is desired that a nucleic acid be delivered. The present invention provides a means of providing to a virus access to cells to which it is desired that a nucleic acid be delivered.
The recent cloning of full length cDNAs for gene products implicated in several muscular dystrophies (Lim et al., 1995, Nature Genetics 11: 257-265; Piccolo et al., 1995, Nature Genetics, 10: 243-245; Nigro et al., 1996, Nature Genetics 14: 195-198; Bonnemann et al., 1995, Nature Genetics 11: 266-273; and Helbling-Leclerc et al., 1995, Nature Genetics 11: 216-218) has been paralleled by improvement in a variety of virus-based vector systems for use in somatic gene transfer (Yang et al., 1994, Nature Genetics 7: 362-369; Yeh et al. 1996, J. Virology 70: 559-565; and Wilson, 1996, New Eng. J. Med. 334:1185-1187). The universal muscle involvement and resulting respiratory insufficiency in these diseases have focussed attention on the need for systemic vector delivery in vivo to animal tissues and organs (Boland et al., 1996, Pediatric Neurology, 14: 7-12; Stedman et al., 1991, Nature 352: 536-539.; Schlenker et al., 1991, J. Appl. Physiol. 71: 1655-1662; and Smith et al., 1987, New Engl. J. Med. 316: 1197-1205). Under physiologic conditions, the continuous endothelium of the skeletal muscle microvasculature is virtually impermeable to proteins larger than albumin (Stokes radius 3.5 nanometers; Berne et al., 1992, In: Physiology, Mosby, St. Louis), and the underlying basal lamina restricts the diffusion of larger macromolecular aggregates (Majno et al., 1961, J. Biophys. Biochem. Cytol. 11:571-597).
There is an acute need to develop compositions and methods which facilitate access of large macromolecules to muscle for the purposes of delivery of compounds which are of therapeutic benefit to mammals in need of such compounds. The present invention satisfies this need.
SUMMARY OF THE INVENTION
The invention relates to a composition for delivering a macromolecular assembly to an extravascular tissue of an animal comprising the macromolecular assembly and a vascular permeability-enhancing agent. In one embodiment, the macromolecular assembly is a gene vector. In another embodiment, the vascular permeability-enhancing agent is selected from the group consisting of histamine, acetylcholine, an adenosine nucleotide, arachidonic acid, bradykinin, cyanide, endothelin, endotoxin, interleukin-2, ionophore A23 187, nitroprusside, a leukotriene, an oxygen radical, phospholipase, platelet activating factor, protamine, serotonin, tumor necrosis factor, vascular endothelial growth factor, a venom, and a vasoactive amine, and is preferably histamine or vascular endothelial growth factor.
In another aspect of the invention, the composition comprises the macromolecular assembly a vascular permeability-enhancing agent, and a vasodilating agent. In one embodiment, the vasodilating agent is selected from the group consisting of papaverine, nimodipine, hydralazine, nitric oxide, epoprostenol, tolazoline, amrinone, milrinone, nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, and an organic nitrate compound, and is preferably papaverine.
In yet another aspect of the invention, the composition comprises the macromolecular assembly a vascular permeability-enhancing agent, and an oxygen-transporting agent.
The invention also provides a kit for providing a macromolecular assembly to an extravascular tissue of an animal. The kit comprises a vascular permeability-enhancing agent and a vasodilating agent. In one embodiment, the kit further comprises the macromolecular assembly. In another embodiment, the macromolecular assembly is a gene vector comprising a human gene selected from the group consisting of a gene encoding dystrophin, a gene encoding eutrophin, a gene encoding a sarcoglycan, and a gene encoding a minidystrophin.
In yet another aspect, the kit comprises a vascular permeability-enhancing agent, a vasodilating agent, and an oxygen-transporting agent.
In a further aspect of the invention, the kit comprises a vascular permeability-enhancing agent, a vasodilating agent, and at least one disposable element of an extracorporeal circulatory support and oxygenation system. In one embodiment, the at least one disposable element is an oxygenator having a hollow body, a liquid inlet in fluid communication with the interior of the body, a liquid outlet in fluid communication with the interior of the body, a gas inlet for providing gas to the interior of a gas chamber, at least one gas-permeable membrane separating the gas chamber from the interior of the body, and a gas outlet for permitting gas to exit from the gas chamber, whereby gas exchange is enabled between a fluid in the interior of the body and a gas in the gas chamber. In another embodiment of the kit comprising an oxygenator, the body is a tube, the gas-permeable membrane comprises polytetrafluoroethylene (PTFE) tubing extending within at least a portion of the tube, and the gas chamber comprises the interior of the PTFE tubing.
The invention further relates to a method of delivering a macromolecular assembly to an extravascular tissue of an animal, preferably a human. The method comprises the steps of providing a vascular permeability-enhancing agent to a blood vessel associated with the tissue to increase the permeability of the endothelial layer of the vessel and providing the macromolecular assembly to the vessel, whereby the assembly is delivered to the tissue through the endothelial layer of the vessel. In one embodiment of the method, the macromolecular assembly is a gene vector, preferably an adenoviral gene vector. The gene vector preferably comprises a human gene, such as a gene selected from the group consisting of a gene encoding human dystrophin, a gene encoding eutrophin, a gene encoding a sarcoglycan, and a gene encoding a minidystrophin. In another embodiment, the gene vector comprises a promoter/regulatory region operably linked to the human gene, wherein the promoter/enhancer region is selected from the group consisting of a human skeletal muscle creatine phosphokinase promoter/regulatory region, a murine skeletal muscle creatine phosphokinase promoter/regulatory region, a promoter/regulatory region of a gene which is ordinarily expressed in a human skeletal muscle cell, and a human constitutive promoter region.
In another aspect of the invention, the method further comprises the step of providing a vasodilating agent to the vessel.
In another aspect of the invention, the tissue to which the macromolecular assembly is delivered is muscle tissue, preferably striated muscle tissue.
In yet another aspect, the method further comprises the step of increasing the perfusion pressure within the vessel above the normal physiological perfusion pressure after providing the macromolecular assembly to the vessel.
In still another aspect, the method further comprises the step of isolating the vessel from the blood circulatory system of the animal prior to providing the macromolecular assembly to the vessel. In one embodiment, the step of isolating the vessel from the blood circulatory system of the animal is performed prior to providing the vascular permeability-enhancing agent to the vessel. In another embodiment, the method further comprises the step of providing a clearance solution to the vessel after providing the macromolecular assembly to the vessel, the clearance solution being substantially free of the vascular permeability-enhancing agent.
In another aspect, the method further comprises the step of providing an oxygen-transporting agent to the vessel after isolating the vessel from the blood circulatory system.
In yet anothe
Akin Gump Strauss Hauer & Feld L.L.P.
McKelvey Terry
The Trustees of the University of Pennsylvania
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