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Patent Application Titled "Methods and Compositions for Treating Conditions of the Eye" Under Review

2013 JAN 11 (NewsRx) -- By a News Reporter-Staff News Editor at Angiogenesis Weekly -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Miller, Joan W. (Winchester, MA); Gragoudas, Evangelos S. (Lexington, MA); Renno, Reem Z. (Boston, MA), filed on March 16, 2012, was cleared for further review on December 27, 2012.

No assignee for this patent application, patent serial number 422462, has been made.

Reporters obtained the following quote from the background information supplied by the inventors: "Choroidal neovascularization can lead to hemorrhage and fibrosis, with resulting visual loss in a number of conditions of the eye, including, for example, age-related macular degeneration, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, and certain inflammatory diseases. One of the disorders, namely, age-related macular degeneration (AMD), is the leading cause of severe vision loss in people aged 65 and above (Bressler et al. (1988) SURV. OPHTHALMOL. 32, 375-413, Guyer et al. (1986) ARCH. OPHTHALMOL. 104, 702-705, Hyman et al. (1983) AM. J. EPIDEMIOL. 188, 816-824, Klein & Klein (1982) ARCH. OPHTHALMOL. 100, 571-573, Leibowitz et al. (1980) SURV. OPHTHALMOL. 24, 335-610). Although clinicopathologic descriptions have been made, little is understood about the etiology and pathogenesis of the disease.

"Dry AMD is the more common form of the disease, characterized by drusen, pigmentary and atrophic changes in the macula, with slowly progressive loss of central vision. Wet or neovascular AMD is characterized by subretinal hemorrhage, fibrosis and fluid secondary to the formation of choroidal neovasculature (CNV), and more rapid and pronounced loss of vision. While less common than dry AMD, neovascular AMD accounts for 80% of the severe vision loss due to AMD. Approximately 200,000 cases of neovascular AMD are diagnosed yearly in the United States alone.

"Currently there is no treatment for dry AMD. Until recently, laser photocoagulation has been the only therapy available for selected cases of neovascular AMD. Unfortunately, the majority of patients with neovascular AMD do not meet the criteria for laser photocoagulation therapy. Approximately 85% of patients with neovascular AMD have poorly defined, occult, or relatively extensive subfoveal choroidal neovascularization, none of which is amenable to laser therapy. In addition, laser photocoagulation relies on thermal damage to the CNV tissue, which damages the overlying neurosensory retina with consequent loss of visual function. Laser photocoagulation also is plagued by recurrences that occur in approximately 50% of cases.

"Photodynamic therapy (PDT) has shown promising results as a new treatment for removing unwanted CNV and for treating neovascular AMD (Miller et al. (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1161-1173, Schmidt-Erfurth et al. (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1177-1187, TAP Study Group (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1329-45, Husain et al. (1999) PHILADELPHIA: MOSBY; 297-307). PDT involves the systemic administration of a photosensitizer or PDT dye (photosensitizer) that accumulates in proliferating tissues such as tumors and newly formed blood vessels; followed by irradiation of the target tissue with low-intensity, non-thermal light at a wavelength corresponding to the absorption peak of the dye (Oleinick et al. (1998) RADIATION RESEARCH; 150: S146-S156). Excitation of the dye leads to the formation of singlet oxygen and free radicals-better known as reactive oxygen species which cause photochemical damage to the target tissue (Weishaupt et al. (1976) CANCER RES. 36: 2326-2329).

"Studies using PDT for the treatment of CNV have demonstrated that, with the proper treatment parameters of photosensitizer dose, laser light dose, and timing of irradiation, relative selective damage to experimental CNV can be achieved, sparing retinal vessels, large choroidal vessels, and with minimal changes in the neurosensory retina (Husain et al. (1996) ARCH OPHTALMOL. 114: 978-985, Husain et al. (1997) SEMINARS IN OPHTHALMOLOGY 12: 14-25, Miller et al. (1995) ARCH OPHTHALMOL. 113: 810-818, Kramer et al. (1996) OPHTHALMOLOGY 103(3): 427-438). Moreover, a PDT-based procedure using a green porphyrin dye recently has been approved in a variety of countries for use in the treatment of neovascular AMD.

"During clinical studies, however, it has been found that recurrence of leakage appears in at least a portion of the CNV by one to three months post-treatment. Increasing photosensitizer or light doses do not appear to prevent this recurrence, and can even lead to undesired non-selective damage to retinal vessels (Miller et al. (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1161-1173). Several multicenter Phase 3 trials are underway to study repeated PDT treatments, applied every three months. The interim data look promising in terms of decreased rates of moderate vision loss (TAP Study Group (1999) ARCHIVES OF OPHTHALMOLOGY 117: 1329-45). The necessity for repeated PDT treatments can nevertheless be expected to lead to cumulative damage to the retinal pigment epithelium (RPE) and choriocapillaris, which may lead to progressive treatment-related vision loss.

"Therefore, there is still a need for improved PDT-based methods that increase the efficacy and selectivity of treatment, and which reduce or delay a recurrence of the disorder."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention is directed to PDT-based methods and compositions for treating ocular conditions associated with unwanted choroidal neovasculature. Such conditions include, for example, neovascular AMD, ocular histoplasmosis syndrome, pathologic myopia, angioid streaks, idiopathic disorders, choroiditis, choroidal rupture, overlying choroid nevi, and certain inflammatory diseases. The invention provides a more effective PDT-based method for treating unwanted CNV that has one or more of the following advantages: increased efficacy of treatment; increased selectivity for CNV; and reduced or delayed recurrence of the condition following PDT.

"In one aspect, the invention provides a method of treating unwanted CNV in a mammal, wherein the CNV comprises endothelial cells, for example, capillary endothelial cells. The method comprises the steps of: (a) administering to the mammal, for example, a primate, preferably, a human, an anti-angiogenesis factor in an amount sufficient to permit an effective amount to localize in the CNV; (b) administering to the mammal an amount of a photosensitizer (PDT dye) sufficient to permit an effective amount to localize in the CNV; and © irradiating the CNV with laser light such that the light is absorbed by the photosensitizer so as to occlude the CNV. During practice of this method, the damage to endothelial cells disposed within the choroidal neovasculature is greater than the damage experienced by endothelial cells in a similar treatment lacking administration of the anti-angiogenesis factor. Furthermore, the anti-angiogenesis factor can potentiate the cytotoxicity of PDT. For example, the anti-angiogenesis factor and the PDT may act synergistically to selectively kill capillary endothelial cells, while at the same time sparing retinal cells, for example, retinal pigment epithelial cells and cells disposed in the neurosensory retina, for example, photoreceptor cells and Mueller cells.

"The anti-angiogenesis factor can enhance the selectivity of the PDT by, for example, occluding the CNV while at the same sparing surrounding blood vessels, for example, normal choroidal and retinal vasculature, and/or tissue, for example, the overlying neurosensory retina. Accordingly, inclusion of the anti-angiogenesis factor makes the PDT method more selective for capillary endothelial cells. Furthermore, practice of the invention can slow down or delay the recurrence of choroidal neovasculature.

"A variety of anti-angiogenesis factors may be used in the invention. Useful anti-angiogenesis factors, include, for example: angiostatin; endostatin; a peptide containing a RGD tripeptide sequence and capable of binding the .alpha.vB integrin, a COX-2 selective inhibitor; halofuginone; anecotave acetate; antibodies and other peptides that bind vascular endothelial growth factor receptor; antibodies, other peptides, and nucleic acids that bind vascular endothelial growth factor to prevent or reduce its binding to its cognate receptor; tyrosine kinase inhibitors; thrombospondin-1; anti-epidermal growth factor; hepatocyte growth factor; thromboxane; and pigment endothelial-derived growth factor. Preferred anti-angiogenic factors include angiostatin, endostatin and pigment epithelium-derived growth factor.

"The anti-angiogenesis factor may, under certain circumstances, be co-administered simultaneously with the photosensitizer. In a preferred embodiment, however, the anti-angiogenesis factor is administered to the mammal prior to administration of the photosensitizer.

"In another aspect, the invention provides a method of treating unwanted CNV in a mammal. The method comprises the steps of: (a) administering to a mammal, for example, a primate, preferably, a human, an amount of a photosensitizer to permit an effective amount to localize in the CNV, the photosensitizer comprising a targeting moiety that binds preferentially to cell surface ligands disposed on endothelial cells, for example, capillary endothelial cells, present in the CNV; and (b) irradiating the CNV with laser light such that the light is absorbed by the photosensitizer so as to occlude the CNV. The targeting moieties bind preferentially to CNV and, therefore, can increase the effective concentration of photosensitizer in the CNV relative to surrounding cells and tissues. Accordingly, such a method increases the selectivity of the PDT method for CNV while sparing surrounding retinal and large choroidal blood vessels and overlying neurosensory retina.

"The targeting moiety can be any molecule, for example, a protein, peptide, nucleic acid, peptidyl-nucleic acid, organic molecule or inorganic molecule that has an affinity for endothelial cells within CNV. However, targeting proteins and peptides are preferred. For example, the targeting peptide can be a peptide that targets .alpha.vB integrin, for example, .alpha.vB 3 integrin or .alpha.vB 5 integrin. Alternatively, the targeting peptide can be an antibody, for example, a monoclonal antibody or an antigen binding fragment thereof, a polyclonal antibody or an antigen binding fragment thereof, or a biosynthetic antibody binding site that binds preferentially to a cell surface ligand disposed at elevated concentrations or densities in CNV. By way of example, the targeting moiety may be an antibody that binds specifically to the vascular endothelial growth factor receptor.

"In another aspect, the invention provides a method of treating unwanted CNV in a mammal. The method comprises the steps of: (a) administering to the mammal, for example, a primate, and more preferably, a human, an apoptosis-modulating factor in an amount sufficient to permit an effective amount to localize in the CNV or tissue surrounding the CNV; (b) administering to the mammal an amount of photosensitizer sufficient to permit an effective amount of localize in the CNV; and © irradiating the CNV with laser light such that the light is absorbed by the photosensitizer so as to occlude the CNV. Cytotoxicity of the PDT can be enhanced and/or made more specific for CNV relative to a similar treatment lacking the apoptosis-modulating factor.

"The apoptosis-modulating factor may be any molecule, for example, a protein, peptide, nucleic acid, peptidyl-nucleic acid, organic molecule or inorganic molecule, that enhances or stimulates apoptosis in cells or tissues of the CNV or that represses apoptosis in cells or tissues surrounding the CNV. In a preferred embodiment, the apoptosis-modulating factor is a peptide capable of inducing apoptosis in cells, for example, endothelial cells, present in CNV. The peptide may comprise, for example, an amino sequence comprising, in an N- to C-terminal direction, KLAKLAKKLAKLAK (SEQ ID NO: 1) which is designed to be non-toxic outside cells, but which is toxic when internalized into target cells because it disrupts mitochondrial membranes. Furthermore, this peptide may be targeted towards endothelial cells by inclusion of a targeting amino acid sequence, for example, in an N- to C-terminal direction, ACDCRGDCFC (SEQ ID NO: 2), also known as RGD-4C.

"The apoptosis-modulating factor may be co-administered simultaneously with the photosensitizer. However, in a preferred embodiment, the apoptosis-modulating factor is administered to the primate before administration of the photosensitizer and/or irradiation.

"In all the foregoing methods, it is contemplated that any photosensitizer useful in PDT may be useful in the practice of the invention. Preferred photosensitizers include, for example, amino acid derivatives, azo dyes, xanthene derivatives, chlorins, tetrapyrrole derivatives, phthalocyanines, and assorted other photosensitizers. However, preferred photosensitizers, include, for example, lutetium texaphyrin, benzoporphyrin and derivatives thereof, and hematoporphyrin and derivatives thereof."

For more information, see this patent application: Miller, Joan W.; Gragoudas, Evangelos S.; Renno, Reem Z. Methods and Compositions for Treating Conditions of the Eye. U.S. Patent Serial Number 422462, filed March 16, 2012, and posted December 27, 2012. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser'Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1450&p=29&f=G&l=50&d=PG01&S1=20121220.PD.&OS=PD/20121220&RS=PD/20121220

Keywords for this news article include: Antibodies, Biotechnology, Patents, Apoptosis, Immunology, Angiogenesis, Blood Proteins, Immunoglobulins, Photocoagulation, Endothelial Growth Factors, Intercellular Signaling Peptides and Proteins.

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