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Materials and methods for treating ocular-related disordersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.)Materials and methods for treating ocular-related disorders description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070098692, Materials and methods for treating ocular-related disorders. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS [0001] This patent application is a continuation of copending U.S. patent application Ser. No. 10/211,701, filed Aug. 2, 2002, which is a continuation of International Patent Application No. PCT/US01/04203, filed Feb. 9, 2001, which designates the U.S., and which claims the benefit of U.S. Provisional Patent Application No. 60/228,337, filed Aug. 28, 2000, and which also claims the benefit of U.S. Provisional Patent Application No. 60/181,743, filed Feb. 11, 2000, and which also is a continuation-in-part of U.S. patent application Ser. No. 09/599,997, filed Jun. 23, 2000, which claims the benefit of U.S. Provisional Patent Application No. 60/181,743, filed Feb. 11, 2000. BACKGROUND OF THE INVENTION [0002] An overwhelming majority of the world's population will experience some degree of vision loss in their lifetime. Vision loss affects virtually all people regardless of age, race, economic or social status, or geographical location. Ocular-related disorders, while often not life threatening, necessitate life-style changes that jeopardize the independence of the afflicted individual. Vision impairment can result from most all ocular disorders, including diabetic retinopathies, proliferative retinopathies, retinal detachment, toxic retinopathies, retinal vascular diseases, retinal degenerations, vascular anomalies, age-related macular degeneration and other acquired disorders, infectious diseases, inflammatory diseases, ocular ischemia, pregnancy-related disorders, retinal tumors, choroidal tumors, choroidal disorders, vitreous disorders, trauma, cataract complications, dry eye, and inflammatory optic neuropathies. [0003] Leading causes of severe vision loss and blindness are ocular-related disorders wherein the vasculature of the eye is damaged or insufficiently regulated. Ocular-related diseases comprising a neovascularization aspect are many and include, for example, exudative age-related macular degeneration, diabetic retinopathy, corneal neovascularization, choroidal neovascularization, neovascular glaucoma, cyclitis, Hippel-Lindau Disease, retinopathy of prematurity, pterygium, histoplasmosis, iris neovascularization, macular edema, glaucoma-associated neovascularization, and the like. It is likely that severe vision loss does not result directly from neovascularization, but the effect of neovascularization on the retina. The retina is a delicate ocular membrane on which images are received. Near the center of the retina is the macula lutea, an oval area of retinal tissue where visual sense is most acute. The retina is most delicate at the fovea centralis, the central depression located in the center of the macula. Damage of the retina, i.e., retinal detachment, retinal tears, or retinal degeneration, is directly connected to vision loss. While a common cause of retinal detachment, retinal tears, and retinal degeneration is abnormal, i.e., uncontrolled, vascularization of various ocular tissues, this is not always the case. Atrophic complications associated with age-related macular degeneration, nonproliferative diabetic retinopathy, and inflammatory ocular damage are not associated with neovascularization, but can result in severe vision loss if not treated. Disorders associated with both neovascular and atrophic components, such as age-related macular degeneration and diabetic retinopathy, are particularly difficult to treat due to the emergence of a wide variety of complications. [0004] Age-related macular degeneration is the leading cause of blindness in patients over 65 years of age. As the elderly population of the world increases, the incidence of age-related macular degeneration is expected to increase dramatically, reaching a predicted 7.5 million cases in the United States alone by the year 2030 (Hyman et al., Am. J. Epidemiol., 118, 213-227 (1983)). Age-related macular degeneration (AMD) is a progressive, degenerative disorder of the eye resulting initially in loss of visual acuity. Complications arising with advanced age-related macular degeneration include atrophic and exudative complications. Atrophic complications stem from retinal pigment epithelial cell loss resulting in atrophy of the retinal pigment epithelium (RPE). Exudative complications include disciform scars (i.e., scarring involving fibrous elements) and neovascularization. Severe vision loss occurs as neovascularization or atrophy disturbs the foveal center (Bressler et al., Ophthalmology, 102, 1206-1211 (1995)). Ultimately, blindness from age-related macular degeneration stems from degeneration of the RPE and the subsequent death of photoreceptors. [0005] Similarly, diabetic retinopathy is subdivided into a nonproliferative stage, which typically occurs first, and a proliferative stage. Vision loss associated with nonproliferative diabetic retinopathy stems from retinal edema, in particular diabetic macular edema, resulting from vascular leakage. Focal and diffuse vascular leakage occurs as a result of microvascular abnormalities, intraretinal microaneurysms, capillary closure, and retinal hemorrhages. Prolonged periods of vascular leakage ultimately lead to thickening of the basement membrane and formation of soft and hard exudates. Nonproliferative diabetic retinopathy is also characterized by loss of retinal pericytes. The proliferative stage of diabetic retinopathy is characterized by neovascularization and fibrovascular growth (i.e., scarring involving glial and fibrous elements) from the retina or optic nerve over the inner surface of the retina or disc or into the vitreous cavity. Retinal neovascularization is the leading cause of vision loss associated with proliferative diabetic retinopathy. [0006] For many ocular-related disorders, no efficient therapeutic options currently are available. Laser photocoagulation involves administering laser burns to various areas of the eye and is used in the treatment of many neovascularization-linked disorders. For example, focal macular photocoagulation is used to treat areas of vascular leakage in the macula (Murphy, Amer. Family Physician, 51(4), 785-796 (1995)). Similarly, neovascularization, in particular, advanced proliferative retinopathy, is commonly treated with scatter or panretinal photocoagulation. However, laser treatment may cause permanent blind spots corresponding to the treated areas. Laser treatment may also cause persistent or recurrent hemorrhage, increase the risk of retinal detachment, or induce neovascularization or fibrosis. With respect to age-related macular degeneration, many patients eventually experience severe vision loss in spite of treatment. Other treatment options for ocular-related disorders include thermotherapy, radiation therapy, surgery, e.g., macular translocation, removal of excess ocular tissue, and the like. However, in most cases, all available treatment options have limited therapeutic effect, require repeated, costly procedures, and/or are associated with dangerous side-effects. [0007] Given the prevalence of ocular-related disorders, there remains a need for an effective prophylactic and therapeutic treatment of ocular-related disorders, in particular those ocular-related disorders associated with both atrophic and neovascular complications, such as diabetic retinopathy and age-related macular degeneration. Accordingly, the present invention provides materials and methods for prophylactically and therapeutically treating ocular-related disorders, including treatment of nonproliferative complications and proliferative complications. This and other advantages of the present invention will become apparent from the detailed description provided herein. BRIEF SUMMARY OF THE INVENTION [0008] The present invention provides a method for the prophylactic or therapeutic treatment of ocular-related disorders. In particular, the present invention provides a method of prophylactically or therapeutically treating an animal for at least one ocular-related disorder, such as ocular neovascularization and age-related macular degeneration. The method comprises contacting an ocular cell with (a) an expression vector comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and the same or different nucleic acid sequence encoding a neurotrophic agent, or (b) different expression vectors, each comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and/or a neurotrophic agent. The nucleic acid sequence encoding the inhibitor of angiogenesis and/or the nucleic acid sequence encoding the neurotrophic agent is (are) expressed, thereby resulting in the production of the inhibitor of angiogenesis and/or the neurotrophic agent to prophylactically or therapeutically treat the animal for an ocular-related disorder. [0009] Preferably, the nucleic acid sequence encoding the inhibitor of angiogenesis and the nucleic acid sequence encoding the neurotrophic agent are the same nucleic acid sequence. More preferably, the nucleic acid sequence encodes a factor comprising both anti-angiogenic and neurotrophic activity. Most preferably, the factor is PEDF. [0010] In addition, the present invention provides a viral vector comprising a nucleic acid sequence encoding pigment epithelium-derived factor (PEDF) or a therapeutic fragment thereof. The nucleic acid sequence is operably linked to regulatory sequences necessary for expression of PEDF or a therapeutic fragment thereof. Preferably, the viral vector is an adenoviral vector or an adeno-associated viral vector. Also preferably, the viral vector further comprises one or more additional nucleic acid sequences encoding therapeutic substances other than PEDF or a therapeutic fragment thereof. DETAILED DESCRIPTION OF THE INVENTION [0011] The present invention is directed to methods of prophylactically or therapeutically treating an animal, preferably a human, for at least one ocular-related disorder. The present invention also provides materials for treating ocular-related disorders. Ocular-related disorders appropriate for treatment using the present inventive materials and methods include, but are not limited to, diabetic retinopathies, proliferative retinopathies, retinopathy of prematurity, retinal vascular diseases, vascular anomalies, age-related macular degeneration and other acquired disorders, endophthalmitis, infectious diseases, inflammatory diseases, AIDS-related disorders, ocular ischemia syndrome, pregnancy-related disorders, peripheral retinal degenerations, retinal degenerations, toxic retinopathies, cataracts, retinal tumors, corneal neovascularization, choroidal tumors, choroidal disorders, choroidal neovascularization, neovascular glaucoma, vitreous disorders, retinal detachment and proliferative vitreoretinopathy, cyclitis, non-penetrating trauma, penetrating trauma, post-cataract complications, Hippel-Lindau Disease, dry eye, inflammatory optic neuropathies, macular edema, pterygium, iris neovascularization, surgical-induced disorders, and the like. [0012] In particular, the present invention provides a method of prophylactically or therapeutically treating an animal for at least one ocular-related disorder, such as ocular neovascularization. The method comprises contacting an ocular cell with an expression vector comprising a nucleic acid sequence encoding at least one inhibitor of angiogenesis and/or at least one neurotrophic agent. Preferably, the method comprises contacting an ocular cell with an expression vector comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and the same or different nucleic acid sequence encoding a neurotrophic agent. Desirably, the nucleic acid sequence encodes at least one inhibitor of angiogenesis and at least one neurotrophic agent. The ocular neovascularization treated by the present inventive method can be neovascularization of the choroid. The choroid is a thin, vascular membrane located under the retina. Abnormal neovascularization of the choroid results from, for example, photocoagulation, anterior ischemic optic neuropathy, Best's disease, choroidal hemangioma, metallic intraocular foreign body, choroidal nonperfusion, choroidal osteomas, choroidal rupture, bacterial endocarditis, choroideremia, chronic retinal detachment, drusen, deposit of metabolic waste material, endogenous Candida endophthalmitis, neovascularization at ora serrata, operating microscope burn, punctate inner choroidopathy, radiation retinopathy, retinal cryoinjury, retinitis pigmentosa, retinochoroidal coloboma, rubella, subretinal fluid drainage, tilted disc syndrome, Taxoplasma retinochoroiditis, tuberculosis, and the like. [0013] Neovascularization of the cornea is also appropriate for treatment by the method of the present invention. The cornea is a projecting, transparent section of the fibrous tunic, the outer most layer of the eye. The outermost layer of the cornea contacts the conjunctiva, while the innermost layer comprises the endothelium of the anterior chamber. Corneal neovascularization stems from, for example, ocular injury, surgery, infection, improper wearing of contact lenses, and diseases such as, for example, corneal dystrophies. [0014] Alternatively, the ocular neovascularization is preferably neovascularization of the retina. Retinal neovascularization is an indication associated with numerous ocular diseases and disorders, many of which are named above. Preferably, the neovascularization of the retina treated in accordance with the present inventive method is associated with diabetic retinopathy. Common causes of retinal neovascularization include ischemia, viral infection, and retinal damage. Neovascularization of the retina can lead to macular edema, subretinal discoloration, scarring, and the like. Complications associated with retina neovascularization stem from breakage and leakage of newly formed blood vessels. Vision is impaired as blood fills the vitreous cavity and is not efficiently removed. Not only is the passage of light impeded, but an inflammatory response to the excess blood and metabolites can cause further damage to ocular tissue. In addition, the new vessels form fibrous scar tissue, which, over time, will disturb the retina causing retinal tears and detachment. [0015] The present invention also provides a method for prophylactically or therapeutically treating an animal for age-related macular degeneration. The method comprises contacting an ocular cell associated with age-related macular degeneration with an expression vector comprising a nucleic acid sequence encoding at least one inhibitor of angiogenesis and/or at least one neurotrophic factor. Desirably, the expression vector comprises a nucleic acid sequence encoding an inhibitor of angiogenesis and a nucleic acid sequence encoding a neurotrophic agent. More desirably, the nucleic acid sequence encoding the inhibitor of angiogenesis and the nucleic acid sequence encoding the neurotrophic agent are the same nucleic acid sequence. Preferably, the age-related macular degeneration is associated with at least one exudative complication. Exudative complications include, for example, disciform scars (i.e., scarring involving fibrous elements) and neovascularization. Alternatively, the age-related macular degeneration is associated with at least one atrophic complication. Atrophic complications include, for instance, the formation of drusen and basal laminar deposits, irregularity of retinal pigmentation, and accumulation of lipofuscin granules. [0016] By "prophylactic" is meant the protection, in whole or in part, against ocular-related disorders, in particular ocular neovascularization or age-related macular degeneration. By "therapeutic" is meant the amelioration of the ocular-related disorder, itself, and the protection, in whole or in part, against further ocular-related disease, in particular ocular neovascularization or age-related macular degeneration. One of ordinary skill in the art will appreciate that any degree of protection from, or amelioration of, an ocular-related disorder is beneficial to a patient. The present invention is particularly advantageous in that a therapeutic agent can be directly applied to affected areas without the harmful side effects of presently employed therapies. [0017] The present inventive methods are useful in the treatment of both acute and persistent, progressive ocular-related disorders. For acute ailments, the expression vector comprising a nucleic acid sequence encoding at least one inhibitor of angiogenesis and/or at least one neurotrophic factor can be administered using a single or multiple applications within a short time period. For persistent ocular-related diseases, such as age-related macular degeneration and diabetic retinopathy, numerous applications of the expression vector may be necessary to realize a therapeutic effect. [0018] One of ordinary skill in the art will appreciate that any of a number of expression vectors known in the art are suitable for use in the present inventive methods. Examples of suitable expression vectors include, for instance, plasmids, plasmid-liposome complexes, and viral vectors, e.g., parvoviral-based vectors (i.e., adeno-associated virus (AAV)-based vectors), retroviral vectors, herpes simplex virus (HSV)-based vectors, AAV-adenoviral chimeric vectors, and adenovirus-based vectors. Any of these expression vectors can be prepared using standard recombinant DNA techniques described in, e.g., Sambrook et al., Molecular Cloning, a Laboratory Manual, 2d edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994). [0019] Plasmids, genetically engineered circular double-stranded DNA molecules, can be designed to contain an expression cassette for delivery of the nucleic acid sequence encoding at least one inhibitor of angiogenesis and/or at least one neurotrophic factor to an ocular cell. Although plasmids were the first vector described for administration of therapeutic nucleic acids, the level of transfection efficiency is poor compared with other techniques. By complexing the plasmid with liposomes, the efficiency of gene transfer in general is improved. While the liposomes used for plasmid-mediated gene transfer strategies have various compositions, they are typically synthetic cationic lipids. Advantages of plasmid-liposome complexes include their ability to transfer large pieces of DNA encoding a therapeutic nucleic acid and their relatively low immunogenicity. [0020] Plasmids are often used for short-term expression. However, a plasmid construct can be modified to obtain prolonged expression. It has recently been discovered that the inverted terminal repeats (ITR) of parvovirus, in particular adeno-associated virus (AAV), are responsible for the high-level persistent nucleic acid expression often associated with AAV (see, for example, U.S. Pat. No. 6,165,754). Accordingly, the expression vector can be a plasmid comprising native parvovirus ITRs to obtain prolonged and substantial expression of at least one inhibitor of angiogenesis and/or at least one neurotrophic factor. While plasmids are suitable for use in the present inventive methods, preferably the expression vector is a viral vector. Continue reading about Materials and methods for treating ocular-related disorders... Full patent description for Materials and methods for treating ocular-related disorders Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Materials and methods for treating ocular-related disorders patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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