Patent Publication Number: US-2018036366-A1

Title: Adminstration of recombinant collagen 7 for the treatment of age related disorders

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a Divisional application of U.S. patent application Ser. No. 14/655,251 filed on Jun. 24, 2015, which is a U.S. National Stage application of PCT/US2013/077479, filed Dec. 23, 2013, which claims the benefit of U.S. Provisional application No. 61/746,421, filed Dec. 27, 2012. The contents of each of which are herein incorporated by reference in their entirety. 
    
    
     REFERENCE TO SEQUENCE LISTING 
     The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled SEQLST2118-1005USDIV.txt, created on Oct. 24, 2017, which is 38,271 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. 
     BACKGROUND OF THE INVENTION 
     Collagen 7 functions to strengthen and stabilize the skin, in that it is a major component of anchoring fibrils (“AFs”), which help anchor the top layer of the skin, the epidermis, to the underlying dermis. Chronically sun-exposed, photodamaged or photoaged skin is relatively fragile compared to sun-protected skin. This fragility has been attributed at least in part to decreased number of anchoring fibrils in the damaged skin caused by decreased collagen 7 mRNA expression in the damaged skin (Woodley et al. (1990)  JAMA  263(22): 3057-3059; Craven et al. (1997)  British Journal of Dermatology  137: 344-350). In addition to regulation of collagen 7 expression at the mRNA level as described above, collagen 7 expression can also be regulated through the expression and activity of collagenases. Collagenases are enzymes that catalyze the break down of collagens through hydrolysis of the peptide bonds in triple helical regions of collagen proteins. Collagen 7 can be reduced at DEJ in areas of skin that are malignant or areas of high statistical risk of skin cancer, e.g., shot exposed skin, aged skin, sun exposed skin; and this may facilitate the intervention. Chronically sun-exposed and sun-protected older skin have also been associated with increased levels of collagenase activity relative to younger skin (Orringer el al. 2004  Arch Dermatol  140: 1326-1332; Fisher et al. 1997  NEJM  337: 1419-1428). 
     SUMMARY OF THE INVENTION 
     The present disclosure is based, at least in part, on the finding that decreased collagen 7 levels occur in the subjects having various disorders, e.g., such as age-related disorders. For example, it has been found that there is decreased collagen 7 expression in the skin of elderly subjects. Accordingly, the disclosure provides, inter alia, methods of treating an elderly subject, having an age related disorder, through the administration of collagen 7 or functional fragments and variants thereof. 
     In one aspect, the disclosure features a method of treating a subject, the method comprising: administering to an elderly subject having or at risk of having an age related disorder, collagen 7 or functional fragments and variants thereof. 
     In certain embodiments, the method further comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based at least in part upon the determination that the subject is an elderly subject. In certain embodiments, the method comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based, at least in part, upon the determination that the subject is elderly and has or is at risk of having an age related disorder. 
     In certain embodiments, the elderly subject is a subject at least 60 years or over, e.g., over the age of 65, over the age of 70, over the age of 75, over the age of 80, over the age of 85, over the age of 90, over the age of 95, over the age of 100, over the age of 105, over the age of 110, or over the age of 115. 
     In certain embodiments, the elderly subject is a subject at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, at least 90 years of age, at least 95 years of age, at least 100 years of age, at least 105 years of age, at least 110 years of age, or at least 115 years of age. 
     In certain embodiments, the elderly subject is between the ages of 60-120, between the ages of 60-110, between the ages of 60-100, between the ages of 60-90, between the ages of 60-80. 
     In certain embodiments, the elderly subject is between the ages of 60-70, between the ages of 70-80, between the ages of 80-90, between the ages of 90-100, between the ages of 100-110, or between the ages of 110-120. 
     In certain embodiments, the elderly subject is between the ages of 60-65, between the ages of 65-70, between the ages of 70-75, between the ages of 75-80, between the ages of 80-85, between the ages of 85-90, between the ages of 90-95, between the ages of 95-100, between the ages of 100-105, or between the ages of 105-110, between the ages of 110-115. 
     In certain embodiments, the subject is below the age 60 and has one or more areas of skin which are prematurely aged, e.g., by habitual sun exposure. 
     In certain embodiments, the age related disorder is a chronic disorder. In certain embodiments the age related disorder is a cancer, e.g., skin cancer; mucosal tissue tearing, e.g., vaginal or anal tearing; chronic or non-healing wound; or diabetes. In certain embodiments, the age related disorder is a skin cancer e.g., skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma. 
     In certain embodiments, the subject is an elderly subject that is at risk for an age-related disorder. For example, the subject has a previous diagnosis of a skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma; the subject is a recipient of an organ transplant, e.g., a solid organ transplant recipient; the subject currently or previously used a tobacco product, e.g., cigarette smoking, cigar smoking, chewing tobacco, dipping or spit tobacco; the subject has a previous or current diagnosis of a chronic or nonhealing wound, e.g., pressure sore, chronic ulcer, or bed sore; the subject has limited mobility; the subject has long term sun exposure, long term daily sun exposure; or a skin type associated with an risk of susceptibility to skin cancer, e.g., skin phototype I, skin phototype II, skin phototype III. 
     In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as a single dose. In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as multiple doses (an initial dose and one or more subsequent doses) over a period of time. 
     In one embodiment, multiple doses of the collagen 7, or the functional fragment or variant thereof, are administered for a period of at least 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, three years, four years, five years, six years or more (e.g., over the remaining lifetime, over a lifetime). 
     In one embodiment, each subsequent dose of collagen 7, or the functional fragment or variant thereof, is administered two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks after the previous dose. In one embodiment, each subsequent dose is administered one month after the previous dose of collagen 7, or the functional fragment or variant thereof. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once a month for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 6 weeks, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 2 months, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered systemically, e.g., intravenously. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered topically, e.g., a cream, ointment, or lotion. 
     In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more additional agents, e.g., a chemotherapeutic agent, immunosuppressants, antibiotics, analgesics, opioids, anti-virals, or anti-inflammatory agents. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent is administered systemically, e.g., intravenously. In some embodiments, the chemotherapeutic agent is administered topically. 
     In one aspect, the disclosure features a method of treating a subject, the method comprising: administering to an elderly subject having a skin cancer or at risk of having a skin cancer, collagen 7 or functional fragments and variants thereof. 
     In certain embodiments, the method further comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based at least in part upon the determination that the subject is an elderly subject. In certain embodiments, the method comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based, at least in part, upon the determination that the subject is elderly and has at least one risk factor for skin cancer. In certain embodiments, the method comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based, at least in part, upon the determination that the subject is elderly and the subject has skin cancer. 
     In certain embodiments, the elderly subject is a subject at least 60 or over, e.g., over the age of 65, over the age of 70, over the age of 75, over the age of 80, over the age of 85, over the age of 90, over the age of 95, over the age of 100, over the age of 105, over the age of 110, or over the age of 115. 
     In certain embodiments, the elderly subject is at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, at least 90 years of age, at least 95 years of age, at least 100 years of age, at least 105 years of age, at least 110 years of age, or at least 115 years of age. 
     In certain embodiments, the elderly subject is between the ages of 60-120, between the ages of 60-110, between the ages of 60-100, between the ages of 60-90, between the ages of 60-80. 
     In certain embodiments, the elderly subject is between the ages of 60-70, between the ages of 70-80, between the ages of 80-90, between the ages of 90-100, between the ages of 100-110, or between the ages of 110-120. 
     In certain embodiments, the elderly subject is between the ages of 60-65, between the ages of 65-70, between the ages of 70-75, between the ages of 75-80, between the ages of 80-85, between the ages of 85-90, between the ages of 90-95, between the ages of 95-100, between the ages of 100-105, or between the ages of 105-110, between the ages of 110-115. 
     In some embodiments, the elderly subject has one or more risk factor for developing a skin cancer. In some embodiments, the elderly subject has one or more, two or more, three or more, four or more, five or more, or six or more risk factors for developing a skin cancer. In some embodiments, the elderly subject has one or more, two or more, three or more, four or more, five or more, or six or more of the following risk factors for developing a skin cancer: a previous diagnosis of a skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma; previous recipient of an organ transplant, e.g., a solid organ transplant recipient; previous or current use of a tobacco product, e.g., cigarette smoking, cigar smoking, chewing tobacco, dipping or spit tobacco; long term sun exposure, long term daily sun exposure; or a skin type associated with an risk of susceptibility to skin cancer, e.g., skin phototype I, skin phototype II, skin phototype III. 
     In some embodiments, the skin cancer is a squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma. In some embodiments, the skin cancer is squamous cell carcinoma. In some embodiments, the skin cancer is associated with the oral mucosa, e.g., lip, tongue, oral cavity, or oropharynx. In some embodiments, the skin cancer is associated with sun protected skin, e.g., parts of the body generally protected from sun exposure, e.g. trunk. In some embodiments, the cancer is associated with non-sun protected skin, e.g., parts of the body generally exposed to the sun, e.g., face, ears, neck, extremities, e.g., back of the hands, arms, legs. 
     In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as a single dose. In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as multiple doses (an initial dose and one or more subsequent doses) over a period of time. 
     In one embodiment, the multiple doses of the collagen 7, or the functional fragment or variant thereof, are administered for a period of at least 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, three years, four years, five years, six years or more (e.g., over a lifetime). 
     In one embodiment, each subsequent dose of collagen 7, or the functional fragment or variant thereof, is administered two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks after the previous dose. In one embodiment, each subsequent dose is administered one month after the previous dose of collagen 7, or the functional fragment or variant thereof. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once a month for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 6 weeks, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 2 months, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered systemically, e.g., intravenously. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered topically, e.g., a cream applied to the site of a skin cancer lesion. 
     In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more additional agents, e.g., a chemotherapeutic agent, an immunotherapeutic agent. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent is administered systemically, e.g., intravenously. In some embodiments, the chemotherapeutic agent is administered topically, e.g., a cream, liquid, or ointment applied to the site of a skin cancer lesion. In one embodiment, the chemotherapeutic agent is 5-flurouracil. In one embodiment, the chemotherapeutic agent is 5-flurouracil for the treatment of premalignant actinic keratosis or squamous cell carcinomas. In some embodiments, the chemotherapeutic agent is imiquimod. In some embodiments, the chemotherapeutic agent is imiquimod for the treatment of the treatment of premalignant actinic keratosis or squamous cell carcinomas. In some embodiments the chemotherapeutic agent is an inhibitor of the hedgehog signaling pathway, e.g., vismodegib. In some embodiments the chemotherapeutic agent is an inhibitor of the hedgehog signaling pathway, e.g., vismodegib, for the treatment of basal cell carcinoma. In some embodiments the chemotherapeutic agent is an inhibitor of the hedgehog signaling pathway, e.g., vismodegib, for the treatment of melanoma. In some embodiments the chemotherapeutic agent is an inhibitor of the hedgehog signaling pathway, e.g., vismodegib, for the treatment of metastatic melanoma. In some embodiments, the chemotherapeutic agent is dacarbazine. In some embodiments, the chemotherapeutic agent is dacarbazine in combination with carmustin and/or tamoxifen. In some embodiments, the chemotherapeutic agent is dacarbazine in combination with cisplatin and/or vinblastine. In some embodiments, the chemotherapeutic agent is temozolomide. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more immunotherapeutic and/or chemotherapeutic agents. In one embodiment, the immunotherapeutic agent is an interferon, e.g., interferon alpha-2b. In one embodiment, the immunotherapeutic agent is tumor necrosis factor. In one embodiment, the immunotherapeutic agent is a lymphokine, e.g., IL-2. In one embodiment, the immunotherapeutic agent is tumor infilitrating lymphokines with or without IL-2. In one embodiment, the immunotherapeutic agent is an anti-CTLA-4 agent, e.g., and anti-CTLA4 antibody, e.g., ipilimumab (MDX-010, MDX-101). In one embodiment, the immunotherapeutic agent is a gene expression inhibiting compound, e.g., PLX4032. 
     In one aspect, the disclosure features a method of treating a subject, the method comprising: administering to an elderly subject having vaginal tearing, e.g., tearing, abrasion, or erosion of the skin around the vagina, e.g., vaginal opening, vaginal tissue; or at risk of having vaginal tearing, collagen 7 or functional fragments and variants thereof. 
     In certain embodiments, the method further comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based at least in part upon the determination that the subject is an elderly subject. In certain embodiments, the method comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based, at least in part, upon the determination that the subject is elderly and has a vaginal tear or at risk of having vaginal tearing. 
     In certain embodiments, the elderly subject is at least 60 or over, e.g., over the age of 65, over the age of 70, over the age of 75, over the age of 80, over the age of 85, over the age of 90, over the age of 95, over the age of 100, over the age of 105, over the age of 110, or over the age of 115. 
     In certain embodiments, the elderly subject is at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, at least 90 years of age, at least 95 years of age, at least 100 years of age, at least 105 years of age, at least 110 years of age, or at least 115 years of age. 
     In certain embodiments, the elderly subject is between the ages of 60-120, between the ages of 60-110, between the ages of 60-100, between the ages of 60-90, between the ages of 60-80. 
     In certain embodiments, the elderly subject is between the ages of 60-70, between the ages of 70-80, between the ages of 80-90, between the ages of 90-100, between the ages of 100-110, or between the ages of 110-120. 
     In certain embodiments, the elderly subject is between the ages of 60-65, between the ages of 65-70, between the ages of 70-75, between the ages of 75-80, between the ages of 80-85, between the ages of 85-90, between the ages of 90-95, between the ages of 95-100, between the ages of 100-105, or between the ages of 105-110, between the ages of 110-115. 
     In some embodiments, the elderly subject has one or more risk factors for vaginal tearing. In some embodiments, the elderly subject has one or more, two or more, three or more, four or more, five or more, or six or more risk factors for developing vaginal tearing. In some embodiments, the elderly subject has one or more, two or more, three or more, four or more, five or more, or six or more of the following risk factors for developing vaginal tearing: a level of estrogen commonly associated with menopause or post menopause, e.g., below 50 pg/ml in a blood sample, below 40 pg/ml in a blood sample, below 30 pg/ml in a blood sample, below 20 pg/ml in a blood sample, below 10 pg/ml in a blood sample; menopausal; post-menopausal; sexually active; not currently receiving estrogen therapy; a contraindication to estrogen therapy, e.g., irregular involuntary spasms of limbs or facial muscles, tobacco smoking, epileptic seizure, migraine headache, a blood clot within the blood vessels of the eye, increased cardiovascular event risk, mammography abnormal, protein c deficiency disease, hyperlipoproteinemia, high blood pressure, severe uncontrolled high blood pressure, heart attack, disease of the arteries of the heart, blood clot in lung, stroke, obstruction of a blood vessel by a blood clot, blood clot in vein, blood clot in a deep vein, asthma, liver problems, disease of the gallbladder, lump in the breast, endometriosis, bleeding not related to menstrual period, yellow-brown patches on skin, systemic lupus erythematosus, pregnancy, uterine fibroids, breast cancer, family history of breast cancer, cancer of the ovary, cancer in the lining of the uterus, tumor that is dependent on estrogen for growth, underactive thyroid, diabetes, high cholesterol, high amount of triglyceride in the blood, low amount of calcium in the blood, high amount of calcium in the blood, water retention, hepatic porphyria, inherited disorder of continuing episodes of swelling, overweight, deficiency of anti-clotting agents, abnormal increase in ability of blood to clot, disorder of mental processes due to a brain disease; cancer, e.g., breast cancer, cancer of the ovary, cancer in the lining of the uterus, a cancer dependent on estrogen for growth, a cancer in remission, e.g., breast cancer, cancer of the ovary, cancer in the lining of the uterus, a cancer dependent on estrogen for growth; an estrogen allergy. 
     In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as a single dose. In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as multiple doses (an initial dose and one or more subsequent doses) over a period of time. 
     In one embodiment, the collagen 7, or the functional fragment or variant thereof, is administered for a period of at least 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, three years, four years, five years, six years or more (e.g., over a lifetime). 
     In one embodiment, each subsequent dose of collagen 7, or the functional fragment or variant thereof, is administered two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks after the previous dose. In one embodiment, each subsequent dose is administered one month after the previous dose of collagen 7, or the functional fragment or variant thereof. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once a month for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 6 weeks, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 2 months, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered systemically, e.g., intravenously. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered topically. 
     In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more additional agents. In some embodiments, the additional agent is a vaginal moisturizer, e.g., a non-estrogen based vaginal moisturizer. In some embodiments, the additional agent is an antidepressant, e.g., a low dose antidepressant, e.g., vanlefaxine (effexor); a selective serotonin uptake inhibitor, e.g., fluoxetine (prozax, sarafem), paroxetine (paxil), citalopram (celexa), sertraline (Zoloft). In one embodiment the additional agent is an agent to which reduces the frewuency or severity of hot flashes, e.g., gabapentin (neurotonin), clonidine. In some embodiments, the additional agent is an anti-osteoporosis agent, e.g., a bisphosphate, e.g., alendronate (Fosamax), risedronate (Actonel) and ibandronate (Boniva). 
     In one aspect, the disclosure features a method of treating a subject, the method comprising: administering to an elderly or chronically ill subject who has had a skin lesion, e.g., a skin cancer, that has been surgically excised, collagen 7 or functional fragments and variants thereof. 
     In certain embodiments, the method further comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based at least in part upon the determination that the subject is an elderly subject or a chronically ill subject. In certain embodiments, the method comprises selecting a subject for administration of collagen 7, or functional fragments or variants thereof, based, at least in part, upon the determination that the subject is elderly and/or chronically ill and has a skin lesion. The method can further comprise removing the skin lesion. 
     In certain embodiments, the elderly subject is at least 60 or over, e.g., over the age of 65, over the age of 70, over the age of 75, over the age of 80, over the age of 85, over the age of 90, over the age of 95, over the age of 100, over the age of 105, over the age of 110, or over the age of 115. 
     In certain embodiments, the elderly subject is at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, at least 90 years of age, at least 95 years of age, at least 100 years of age, at least 105 years of age, at least 110 years of age, or at least 115 years of age. 
     In certain embodiments, the elderly subject is between the ages of 60-120, between the ages of 60-110, between the ages of 60-100, between the ages of 60-90, between the ages of 60-80. 
     In certain embodiments, the elderly subject is between the ages of 60-70, between the ages of 70-80, between the ages of 80-90, between the ages of 90-100, between the ages of 100-110, or between the ages of 110-120. 
     In certain embodiments, the elderly subject is between the ages of 60-65, between the ages of 65-70, between the ages of 70-75, between the ages of 75-80, between the ages of 80-85, between the ages of 85-90, between the ages of 90-95, between the ages of 95-100, between the ages of 100-105, or between the ages of 105-110, between the ages of 110-115. 
     In some embodiments, the skin lesion is unable to be or is not recommended to be surgically closed after excision, e.g., a burn, an infected skin lesion, e.g., bacterially infected skin lesion. In some embodiments, the excision is followed by secondary wound closure (i.e., open healing, closure by secondary intention), e.g., the skin edges of the excision are not sutured together, but left open. 
     In some embodiments, the skin lesion is a benign skin lesion. In some embodiments, the skin lesion is a malignant skin lesion. In some embodiments, the skin lesion is a skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma or Kaposi&#39;s sarcoma. In some embodiments, the skin lesion is a burn, an infected skin lesion, e.g., bacterially infected skin lesion. 
     In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as a single dose. In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as multiple doses (an initial dose and one or more subsequent doses) over a period of time. 
     In one embodiment, multiple doses of the collagen 7, or the functional fragment or variant thereof, are administered for a period of at least 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, three years, four years, five years, six years or more (e.g., over a lifetime). 
     In one embodiment, each subsequent dose of collagen 7, or the functional fragment or variant thereof, is administered two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks after the previous dose. In one embodiment, each subsequent dose is administered one month after the previous dose of collagen 7, or the functional fragment or variant thereof. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once a month for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 6 weeks, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 2 months, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered systemically, e.g., intravenously. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered topically. 
     In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more additional agents, e.g., chemotherapeutic agents, immunosuppressants, antibiotics, analgesics, opioids, anti-virals, or anti-inflammatory agents. 
     In one aspect, the disclosure features a method of treating a subject at risk of having cancer, e.g., skin cancer, the method comprising: selecting a subject that has received an organ transplant, and administering collagen 7 or functional fragments and variants thereof. 
     In some embodiments, the organ transplant is a solid organ transplant, e.g., heart, liver, kidney, lung, pancreas, intestine, stomach, testis etc. as contrasted to liquid transplanted tissues, e.g., bone marrow, pancreatic islets, etc. 
     In some embodiments the subject is elderly. In certain embodiments, the elderly subject is a subject at least 60 or over, e.g., over the age of 65, over the age of 70, over the age of 75, over the age of 80, over the age of 85, over the age of 90, over the age of 95, over the age of 100, over the age of 105, over the age of 110, or over the age of 115. 
     In certain embodiments, the elderly subject is at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, at least 90 years of age, at least 95 years of age, at least 100 years of age, at least 105 years of age, at least 110 years of age, or at least 115 years of age. 
     In certain embodiments, the elderly subject is between the ages of 60-120, between the ages of 60-110, between the ages of 60-100, between the ages of 60-90, between the ages of 60-80. 
     In certain embodiments, the elderly subject is between the ages of 60-70, between the ages of 70-80, between the ages of 80-90, between the ages of 90-100, between the ages of 100-110, or between the ages of 110-120. 
     In certain embodiments, the elderly subject is between the ages of 60-65, between the ages of 65-70, between the ages of 70-75, between the ages of 75-80, between the ages of 80-85, between the ages of 85-90, between the ages of 90-95, between the ages of 95-100, between the ages of 100-105, or between the ages of 105-110, between the ages of 110-115. 
     In certain embodiments, the subject has been diagnosed with a skin cancer, e.g., a squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma. 
     In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as a single dose. In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as multiple doses (an initial dose and one or more subsequent doses) over a period of time. 
     In one embodiment, multiple doses of the collagen 7, or the functional fragment or variant thereof, are administered for a period of at least 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, three years, four years, five years, six years or more (e.g., over a lifetime). 
     In one embodiment, each subsequent dose of collagen 7, or the functional fragment or variant thereof, is administered two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks after the previous dose. In one embodiment, each subsequent dose is administered one month after the previous dose of collagen 7, or the functional fragment or variant thereof. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once a month for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 6 weeks, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 2 months, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered systemically, e.g., intravenously. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered topically, e.g., a cream applied to the site of a skin cancer lesion. 
     In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more additional agents. In some embodiments the additional agent includes one or more of an immunosuppressant agent; an infection fighting agent, e.g., an antibiotic, anti-viral, anti-fungal; and or a nutritional supplement. In some embodiments, the additional agent is an immunosuppressant, e.g., steroids, cyclosporine A, azathioprine, prednisone, FK 506, mycophenolate mofetil, tacrolimus, muromonab-CD3, daclizumab. In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with an immunosuppressant and an infection fighting agent, e.g., an antibiotic, anti-viral, or anti-fungal. In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with an immunosuppressant and a nutritional supplement, e.g., a vitamin, iron, magnesium, calcium supplement. 
     In one aspect, the disclosure features a method of treating a subject, the method comprising: selecting a subject diagnosed with a disorder in which the treatment of the disorder is an organ transplant, and administering to the subject collagen 7 or functional fragments and variants thereof. 
     In some embodiments, the subject is diagnosed with failure of a solid organ, e.g., kidney failure, heart failure, liver failure, lung failure, pancreatic failure; or diagnosed with a disorder which would lead to failure of a solid organ, e.g., cancer of a solid organ, e.g., liver cancer, lung cancer, pancreatic cancer; kidney cancer, testicular cancer, intestinal cancer, stomach cancer, heart cancer; chronic renal failure; acute renal failure; type 1 diabetes; type 2 diabetes; chronic kidney disease; immune system conditions, e.g., lupus, chronic viral illnesses, e.g., HIV/AIDS, hepatitis B, hepatitis C; urine blockage in the kidneys; kidney damage; impaired blood flow to the kidneys; congestive heart failure; coronary artery disease; high blood pressure; faulty heart valves; cardiomyopathy; myocarditis; heart arrhythmias; acute heart failure; chronic heart failure; liver failure; liver cirrhosis; biliary duct atresia; cystic fibrosis; early stage liver cancer; primary biliary cirrhosis; primary sclerosing cholangitis; Wilson&#39;s disease; lung cancer. 
     In some embodiments the subject is elderly. In certain embodiments, the elderly subject is at least 60 or over, e.g., over the age of 55, over the age of 70, over the age of 75, over the age of 80, over the age of 85, over the age of 90, over the age of 95, over the age of 100, over the age of 105, over the age of 110, or over the age of 115. 
     In certain embodiments, the elderly subject is at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 85 years of age, at least 90 years of age, at least 95 years of age, at least 100 years of age, at least 105 years of age, at least 110 years of age, or at least 115 years of age. 
     In certain embodiments, the elderly subject is between the ages of 60-120, between the ages of 60-110, between the ages of 60-100, between the ages of 60-90, between the ages of 60-80. 
     In certain embodiments, the elderly subject is between the ages of 60-70, between the ages of 70-80, between the ages of 80-90, between the ages of 90-100, between the ages of 100-110, or between the ages of 110-120. 
     In certain embodiments, the elderly subject is between the ages of 60-65, between the ages of 65-70, between the ages of 70-75, between the ages of 75-80, between the ages of 80-85, between the ages of 85-90, between the ages of 90-95, between the ages of 95-100, between the ages of 100-105, or between the ages of 105-110, between the ages of 110-115. 
     In certain embodiments, the subject has been diagnosed with a skin cancer, e.g., a squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma. 
     In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as a single dose. In some embodiments, the collagen 7, or the functional fragment or variant thereof, is administered as multiple doses (an initial dose and one or more subsequent doses) over a period of time. 
     In one embodiment, the multiple doses of the collagen 7, or the functional fragment or variant thereof, are administered for a period of at least 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 2 years, three years, four years, five years, six years or more (e.g., over a lifetime). 
     In one embodiment, each subsequent dose of collagen 7, or the functional fragment or variant thereof, is administered two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks after the previous dose. In one embodiment, each subsequent dose is administered one month after the previous dose of collagen 7, or the functional fragment or variant thereof. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once a month for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 6 weeks, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered once every 2 months, for at least 3 months, e.g., at least 4, 5, 6, 9, 12, 15, 18, 24, 27, 30, 33, 36, 39, 42, 45 or 48 months or more. 
     In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered systemically, e.g., intravenously. In one embodiment, the collagen 7, or functional fragment or variant thereof, is administered topically, e.g., a cream applied to the site of a skin cancer lesion. 
     In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with one or more additional agents. In some embodiments the additional agent includes one or more of an immunosuppressant agent; an infection fighting agent, e.g., an antibiotic, anti-viral, anti-fungal; and or a nutritional supplement. In some embodiments, the additional agent is an immunosuppressant, e.g., steroids, cyclosporine A, azathioprine, prednisone, FK 506, mycophenolate mofetil, tacrolimus, muromonab-CD3, daclizumab. In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with an immunosuppressant and an infection fighting agent, e.g., an antibiotic, anti-viral, or anti-fungal. In some embodiments, the collagen 7, or functional fragment or variant thereof, is administered in combination with an immunosuppressant and a nutritional supplement, e.g., a vitamin, iron, magnesium, calcium supplement. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Certain terms are first defined. Additional terms are defined throughout the specification. 
     A “chronic” or “non-healing” wound as used herein, refers to a wound that does not heal in an amount of time considered predictable by those skilled in the art for the characteristics of the wound. Chronic wounds are those that do not progress through the usual phases of healing. Examples of common chronic wounds can include, pressure sores, chronic ulcers, bed sores, burn wounds, lower extremity ulcers, lower extremity venous ulcers, lower extremity stasis ulcers, surgical wounds, diabetic ulcers, arterial wounds, and radiation ulcers. 
     A “chronically ill” subject as used herein, refers to a subject diagnosed with a chronic disorder. 
     A “chronic disorder”, as used herein, refers to a disorder of long duration and, often, of generally slow progression. Such disorder include those that require continued therapy, e.g., for at least one year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or for the rest of the patient&#39;s life. Exemplary chronic disorders can include diabetes, cardiovascular disease, chronic respiratory diseases, lupus, multiple sclerosis, AIDS. 
     “Chronic administration”, as used herein, refers to the administration of more than one dose of an agent over a period of time. Chronic administration can include regular administration for an extended period of time. Chronic administration can also include the administration of therapy over a prolonged period of time (in some cases, for the duration of a subject&#39;s lifetime) so that the concentration of the therapeutic agent is maintained at a therapeutically or prophylactically effective level throughout the course of treatment. 
     An “effective amount” of collagen 7 or functional fragment or variant thereof refers to the amount of collagen 7 or functional fragment or variant thereof, when administered in an aggregate of multiple doses, or as part of any other type of defined treatment regimen, produces a measureable statistical improvement in outcome, as evidenced by at least one clinical parameter associated with the complication. 
     “Recombinant”, as used herein, in reference to a protein or polypeptide molecule, pertains to a protein or polypeptide molecule expressed utilizing isolated nucleic acid molecules or recombinant nucleic acid molecules. 
     A skin type associated with a higher than average risk of developing skin cancer can include skin phototypes I, II, and II as described herein. Skin type can be classified into six skin phototypes. Phototypes I and II are associated with the highest risk of skin cancer. Phototype I is described as skin which always burns and does not tan when exposed to the sun, e.g., exposed to 30 minutes of sun light. Phototype II is described as skin which almost always or usually burns and rarely tans when exposed to the sun. Phototype III is described as skin which sometimes burns and sometimes tans when exposed to the sun. Phototype IV is described as skin which tends to tan easily and is less likely to burn when exposed to sun. Phototype V and VI are described as skin which tans easily and rarely burns when exposed to the sun, e.g., Hispanic skin, Black skin, e.g., African American skin, aboriginal skin. 
     “Collagen 7” as used herein refers to collagen type 7 encoded by the COL7A1 gene. Collagen 7 consists of 2,944 amino acids. It comprises a non-collagenous NC1 domain (residues 1-1253), the central collagenous helical domain (residues 1254-2783), and the carboxyl-terminal NC2 domain (residues 2784-2944). 
     A functional fragment of collagen 7 refers to a portion of collagen 7 that maintains the ability to form anchoring fibrils between the epidermal and dermal layers of human skin, and the ability to bind collagen 4 and laminin-332. For example, a functional fragment can include all or a portion of the NC1 domain and/or the NC2 domain of collagen 7, e.g., the functional fragment can be collagen 7 without all of a portion of the central collagenous helical domain, e.g., a fragment that does not include amino acid residues 1920-2603 of the central collagenous helical domain of collagen 7. 
     A variant of collagen 7 refers to a polypeptide that has substantial identity with collagen 7 that maintains the ability to form anchoring fibrils between the epidermal and dermal layers of human skin. Collagen 7 variants include, but are not limited to, collagen 7 polypeptides that have been either chemically modified relative to collagen 7 and/or contain one or more amino acid sequence alterations relative to collagen 7. 
     Variants of collagen 7 include polypeptides having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence of human collagen 7 (SEQ ID NO:2). Calculations of “identity” or “sequence homology” between two sequences (the terms are used interchangeably herein) are performed as follows. The sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The optimal alignment is determined as the best score using the GAP program in the GCG software package with a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences. 
     Variants of collagen 7 also include polypeptides having amino acid modifications (e.g., deletions, additions or substitutions, such as conservative substations) from the amino acid sequence of collagen 7 (SEQ ID NO:2). For example, a variant of collagen 7 can differ by at least 1, 2, 3, 4, 5 but not more than 50, 40, 30, 20, 15 or 10 amino acids from collagen 7 (SEQ ID NO:2). A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). 
     “Collagen 7 composition” refers to a plurality of collagen 7 polypeptides or collagen 7 equivalent polypeptides, or functional fragments or variants of collagen 7, including variants and chemically modified forms that have been separated from the cell in which they were synthesized. An “isolated composition” refers to a composition that is removed from at least 90% of at least one component of a natural sample from which the isolated composition can be obtained. Compositions produced artificially or naturally can be “compositions of at least” a certain degree of purity if the species or population of species of interests is at least 5, 10, 25, 50, 75, 80, 90, 92, 95, 98, or 99% pure on a weight-weight basis. 
     An “isolated” protein refers to a protein that is removed from at least 90% of at least one component of a natural sample from which the isolated protein can be obtained. Proteins can be “of at least” a certain degree of purity if the species or population of species of interest is at least 5, 10, 25, 50, 75, 80, 90, 92, 95, 98, or 99% pure on a weight-weight basis. 
     The term “preventing” a disease in a subject refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is prevented, that is, administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) so that it protects the host against developing the unwanted condition. “Preventing” a disease may also be referred to as “prophylaxis” or “prophylactic treatment.” 
     “Treating” or “treating” a subject having a disorder, refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of a drug, such that at least one symptom of the disease is cured, alleviated or decreased. 
     A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the protein to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects. 
     A “patient”, “subject” or “host” (these terms are used interchangeably) to be treated by the subject method may mean either a human or non-human animal. 
     Any of the treatments described herein can be administered in combination with another agent or therapy. The term “combination” refers to the use of the two or more agents or therapies to treat the same patient, wherein the use or action of the agents or therapies overlap in time. The agents or therapies can be administered at the same time (e.g., as a single formulation that is administered to a patient or as two separate formulations administered concurrently) or sequentially in any order. 
     Collagen 7 
     As a major component of anchoring fibrils, collagen 7 functions in maintaining tissue integrity. Anchoring fibrils are structural elements that serve as attachment complexes at the interface between the epithelial and mesenchymal layers of several tissues, including the skin, oral mucosa, and cervix (Chung et al.  Dermatol Clin  28(1): 93-105 (2010)). In the skin, anchoring fibrils extend from the lower portion of the epidermal basement membrane to the underlying papillary dermis, securing the association between the epidermal basement membrane and the papillary dermis (Varki et al.  J Med Genet  44:181-192 (2007)). This association aids to provide and maintain cohesion between the epidermis and dermis, contributing to the integrity to the skin, which is critical for its proper structure, function, and homeostasis (Villone et al.  J Blot Chem  283(36): 24506-24513 (2008)). The Collagen 7 nucleotide and amino acid sequences are known in the art. An exemplary nucleotide and amino acid sequence for human Collagen 7 is provided herein as SEQ ID NO:1 and SEQ ID NO:2, respectively. 
     
       
         
           
               
               
            
               
                 NCBI Reference Sequence: NM_000094 
                   
               
               
                 (SEQ ID NO: 1) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 gatgacgctg cggcttctgg tggccgcgct ctgcgccggg atcctggcag aggcgccccg 
                   
               
               
                   
               
               
                   61 
                 agtgcgagcc cagcacaggg agagagtgac ctgcacgcgc ctttacgccg ctgacattgt 
               
               
                   
               
               
                  121 
                 gttcttactg gatggctcct catccattgg ccgcagcaat ttccgcgagg tccgcagctt 
               
               
                   
               
               
                  181 
                 tctcgaaggg ctggtgctgc ctttctctgg agcagccagt gcacagggtg tgcgctttgc 
               
               
                   
               
               
                  241 
                 cacagtgcag tacagcgatg acccacggac agagttcggc ctggatgcac ttggctctgg 
               
               
                   
               
               
                  301 
                 gggtgatgtg atccgcgcca tccgtgagct tagctacaag gggggcaaca ctcgcacagg 
               
               
                   
               
               
                  361 
                 ggctgcaatt ctccatgtgg ctgaccatgt cttcctgccc cagctggccc gacctggtgt 
               
               
                   
               
               
                  421 
                 ccccaaggtc tgcatcctga tcacagacgg gaagtcccag gacctggtgg acacagctgc 
               
               
                   
               
               
                  481 
                 ccaaaggctg aaggggcagg gggtcaagct atttgctgtg gggatcaaga atgctgaccc 
               
               
                   
               
               
                  541 
                 tgaggagctg aagcgagttg cctcacagcc caccagtgac ttcttcttct tcgtcaatga 
               
               
                   
               
               
                  601 
                 cttcagcatc ttgaggacac tactgcccct cgtttcccgg agagtgtgca cgactgctgg 
               
               
                   
               
               
                  661 
                 tggcgtgcct gtgacccgac ctccggatga ctcgacctct gctccacgag acctggtgct 
               
               
                   
               
               
                  721 
                 gtctgagcca agcagccaat ccttgagagt acagtggaca gcggccagtg gccctgtgac 
               
               
                   
               
               
                  781 
                 tggctacaag gtccagtaca ctcctctgac ggggctggga cagccactgc cgagtgagcg 
               
               
                   
               
               
                  841 
                 gcaggaggtg aacgtcccag ctggtgagac cagtgtgcgg ctgcggggtc tccggccact 
               
               
                   
               
               
                  901 
                 gaccgagtac caagtgactg tgattgccct ctacgccaac agcatcgggg aggctgtgag 
               
               
                   
               
               
                  961 
                 cgggacagct cggaccactg ccctagaagg gccggaactg accatccaga ataccacagc 
               
               
                   
               
               
                 1021 
                 ccacagcctc ctggtggcct ggcggagtgt gccaggtgcc actggctacc gtgtgacatg 
               
               
                   
               
               
                 1081 
                 gcgggtcctc agtggtgggc ccacacagca gcaggagctg ggccctgggc agggttcagt 
               
               
                   
               
               
                 1141 
                 gttgctgcgt gacttggagc ctggcacgga ctatgaggtg accgtgagca ccctatttgg 
               
               
                   
               
               
                 1201 
                 ccgcagtgtg gggcccgcca cttccctgat ggctcgcact gacgcttctg ttgagcagac 
               
               
                   
               
               
                 1261 
                 cctgcgcccg gtcatcctgg gccccacatc catcctcctt tcctggaact tggtgcctga 
               
               
                   
               
               
                 1321 
                 ggcccgtggc taccggttgg aatggcggcg tgagactggc ttggagccac cgcagaaggt 
               
               
                   
               
               
                 1381 
                 ggtactgccc tctgatgtga cccgctacca gttggatggg ctgcagccgg gcactgagta 
               
               
                   
               
               
                 1441 
                 ccgcctcaca ctctacactc tgctggaggg ccacgaggtg gccacccctg caaccgtggt 
               
               
                   
               
               
                 1501 
                 tcccactgga ccagagctgc ctgtgagccc tgtaacagac ctgcaagcca ccgagctgcc 
               
               
                   
               
               
                 1561 
                 cgggcagcgg gtgcgagtgt cctggagccc agtccctggt gccacccagt accgcatcat 
               
               
                   
               
               
                 1621 
                 tgtgcgcagc acccaggggg ttgagcggac cctggtgctt cctgggagtc agacagcatt 
               
               
                   
               
               
                 1681 
                 cgacttggat gacgttcagg ctgggcttag ctacactgtg cgggtgtctg ctcgagtggg 
               
               
                   
               
               
                 1741 
                 tccccgtgag ggcagtgcca gtgtcctcac tgtccgccgg gagccggaaa ctccacttgc 
               
               
                   
               
               
                 1801 
                 tgttccaggg ctgcgggttg tggtgtcaga tgcaacgcga gtgagggtgg cctggggacc 
               
               
                   
               
               
                 1861 
                 cgtccctgga gccagtggat ttcggattag ctggagcaca ggcagtggtc cggagtccag 
               
               
                   
               
               
                 1921 
                 ccagacactg cccccagact ctactgccac agacatcaca gggctgcagc ctggaaccac 
               
               
                   
               
               
                 1981 
                 ctaccaggtg gctgtgtcgg tactgcgagg cagagaggag ggccctgctg cagtcatcgt 
               
               
                   
               
               
                 2041 
                 ggctcgaacg gacccactgg gcccagtgag gacggtccat gtgactcagg ccagcagctc 
               
               
                   
               
               
                 2101 
                 atctgtcacc attacctgga ccagggttcc tggcgccaca ggatacaggg tttcctggca 
               
               
                   
               
               
                 2161 
                 ctcagcccac ggcccagaga aatcccagtt ggtttctggg gaggccacgg tggctgagct 
               
               
                   
               
               
                 2221 
                 ggatggactg gagccagata ctgagtatac ggtgcatgtg agggcccatg tggctggcgt 
               
               
                   
               
               
                 2281 
                 ggatgggccc cctgcctctg tggttgtgag gactgcccct gagcctgtgg gtcgtgtgtc 
               
               
                   
               
               
                 2341 
                 gaggctgcag atcctcaatg cttccagcga cgttctacgg atcacctggg taggggtcac 
               
               
                   
               
               
                 2401 
                 tggagccaca gcttacagac tggcctgggg ccggagtgaa ggcggcccca tgaggcacca 
               
               
                   
               
               
                 2461 
                 gatactccca ggaaacacag actctgcaga gatccggggt ctcgaaggtg gagtcagcta 
               
               
                   
               
               
                 2521 
                 ctcagtgcga gtgactgcac ttgtcgggga ccgcgagggc acacctgtct ccattgttgt 
               
               
                   
               
               
                 2581 
                 cactacgccg cctgaggctc cgccagccct ggggacgctt cacgtggtgc agcgcgggga 
               
               
                   
               
               
                 2641 
                 gcactcgctg aggctgcgct gggagccggt gcccagagcg cagggcttcc ttctgcactg 
               
               
                   
               
               
                 2701 
                 gcaacctgag ggtggccagg aacagtcccg ggtcctgggg cccgagctca gcagctatca 
               
               
                   
               
               
                 2761 
                 cctggacggg ctggagccag cgacacagta ccgcgtgagg ctgagtgtcc tagggccagc 
               
               
                   
               
               
                 2821 
                 tggagaaggg ccctctgcag aggtgactgc gcgcactgag tcacctcgtg ttccaagcat 
               
               
                   
               
               
                 2881 
                 tgaactacgt gtggtggaca cctcgatcga ctcggtgact ttggcctgga ctccagtgtc 
               
               
                   
               
               
                 2941 
                 cagggcatcc agctacatcc tatcctggcg gccactcaga ggccctggcc aggaagtgcc 
               
               
                   
               
               
                 3001 
                 tgggtccccg cagacacttc cagggatctc aagctcccag cgggtgacag ggctagagcc 
               
               
                   
               
               
                 3061 
                 tggcgtctct tacatcttct ccctgacgcc tgtcctggat ggtgtgcggg gtcctgaggc 
               
               
                   
               
               
                 3121 
                 atctgtcaca cagacgccag tgtgcccccg tggcctggcg gatgtggtgt tcctaccaca 
               
               
                   
               
               
                 3181 
                 tgccactcaa gacaatgctc accgtgcgga ggctacgagg agggtcctgg agcgtctggt 
               
               
                   
               
               
                 3241 
                 gttggcactt gggcctcttg ggccacaggc agttcaggtt ggcctgctgt cttacagtca 
               
               
                   
               
               
                 3301 
                 tcggccctcc ccactgttcc cactgaatgg ctcccatgac cttggcatta tcttgcaaag 
               
               
                   
               
               
                 3361 
                 gatccgtgac atgccctaca tggacccaag tgggaacaac ctgggcacag ccgtggtcac 
               
               
                   
               
               
                 3421 
                 agctcacaga tacatgttgg caccagatgc tcctgggcgc cgccagcacg taccaggggt 
               
               
                   
               
               
                 3481 
                 gatggttctg ctagtggatg aacccttgag aggtgacata ttcagcccca tccgtgaggc 
               
               
                   
               
               
                 3541 
                 ccaggcttct gggcttaatg tggtgatgtt gggaatggct ggagcggacc cagagcagct 
               
               
                   
               
               
                 3601 
                 gcgtcgcttg gcgccgggta tggactctgt ccagaccttc ttcgccgtgg atgatgggcc 
               
               
                   
               
               
                 3661 
                 aagcctggac caggcagtca gtggtctggc cacagccctg tgtcaggcat ccttcactac 
               
               
                   
               
               
                 3721 
                 tcagccccgg ccagagccct gcccagtgta ttgtccaaag ggccagaagg gggaacctgg 
               
               
                   
               
               
                 3781 
                 agagatgggc ctgagaggac aagttgggcc tcctggcgac cctggcctcc cgggcaggac 
               
               
                   
               
               
                 3841 
                 cggtgctccc ggcccccagg ggccccctgg aagtgccact gccaagggcg agaggggctt 
               
               
                   
               
               
                 3901 
                 ccctggagca gatgggcgtc caggcagccc tggccgcgcc gggaatcctg ggacccctgg 
               
               
                   
               
               
                 3961 
                 agcccctggc ctaaagggct ctccagggtt gcctggccct cgtggggacc cgggagagcg 
               
               
                   
               
               
                 4021 
                 aggacctcga ggcccaaagg gggagccggg ggctcccgga caagtcatcg gaggtgaagg 
               
               
                   
               
               
                 4081 
                 acctgggctt cctgggcgga aaggggaccc tggaccatcg ggcccccctg gacctcgtgg 
               
               
                   
               
               
                 4141 
                 accactgggg gacccaggac cccgtggccc cccagggctt cctggaacag ccatgaaggg 
               
               
                   
               
               
                 4201 
                 tgacaaaggc gatcgtgggg agcggggtcc ccctggacca ggtgaaggtg gcattgctcc 
               
               
                   
               
               
                 4261 
                 tggggagcct gggctgccgg gtcttcccgg aagccctgga ccccaaggcc ccgttggccc 
               
               
                   
               
               
                 4321 
                 ccctggaaag aaaggagaaa aaggtgactc tgaggatgga gctccaggcc tcccaggaca 
               
               
                   
               
               
                 4381 
                 acctgggtct ccgggtgagc agggcccacg gggacctcct ggagctattg gccccaaagg 
               
               
                   
               
               
                 4441 
                 tgaccggggc tttccagggc ccctgggtga ggctggagag aagggcgaac gtggaccccc 
               
               
                   
               
               
                 4501 
                 aggcccagcg ggatcccggg ggctgccagg ggttgctgga cgtcctggag ccaagggtcc 
               
               
                   
               
               
                 4561 
                 tgaagggcca ccaggaccca ctggccgcca aggagagaag ggggagcctg gtcgccctgg 
               
               
                   
               
               
                 4621 
                 ggaccctgca gtggtgggac ctgctgttgc tggacccaaa ggagaaaagg gagatgtggg 
               
               
                   
               
               
                 4681 
                 gcccgctggg cccagaggag ctaccggagt ccaaggggaa cggggcccac ccggcttggt 
               
               
                   
               
               
                 4741 
                 tcttcctgga gaccctggcc ccaagggaga ccctggagac cggggtccca ttggccttac 
               
               
                   
               
               
                 4801 
                 tggcagagca ggacccccag gtgactcagg gcctcctgga gagaagggag accctgggcg 
               
               
                   
               
               
                 4861 
                 gcctggcccc ccaggacctg ttggcccccg aggacgagat ggtgaagttg gagagaaagg 
               
               
                   
               
               
                 4921 
                 tgacgagggt cctccgggtg acccgggttt gcctggaaaa gcaggcgagc gtggccttcg 
               
               
                   
               
               
                 4981 
                 gggggcacct ggagttcggg ggcctgtggg tgaaaaggga gaccagggag atcctggaga 
               
               
                   
               
               
                 5041 
                 ggatggacga aatggcagcc ctggatcatc tggacccaag ggtgaccgtg gggagccggg 
               
               
                   
               
               
                 5101 
                 tcccccagga cccccgggac ggctggtaga cacaggacct ggagccagag agaagggaga 
               
               
                   
               
               
                 5161 
                 gcctggggac cgcggacaag agggtcctcg agggcccaag ggtgatcctg gcctccctgg 
               
               
                   
               
               
                 5221 
                 agcccctggg gaaaggggca ttgaagggtt tcggggaccc ccaggcccac agggggaccc 
               
               
                   
               
               
                 5281 
                 aggtgtccga ggcccagcag gagaaaaggg tgaccggggt ccccctgggc tggatggccg 
               
               
                   
               
               
                 5341 
                 gagcggactg gatgggaaac caggagccgc tgggccctct gggccgaatg gtgctgcagg 
               
               
                   
               
               
                 5401 
                 caaagctggg gacccaggga gagacgggct tccaggcctc cgtggagaac agggcctccc 
               
               
                   
               
               
                 5461 
                 tggcccctct ggtccccctg gattaccggg aaagccaggc gaggatggca aacctggcct 
               
               
                   
               
               
                 5521 
                 gaatggaaaa aacggagaac ctggggaccc tggagaagac gggaggaagg gagagaaagg 
               
               
                   
               
               
                 5581 
                 agattcaggc gcctctggga gagaaggtcg tgatggcccc aagggtgagc gtggagctcc 
               
               
                   
               
               
                 5641 
                 tggtatcctt ggaccccagg ggcctccagg cctcccaggg ccagtgggcc ctcctggcca 
               
               
                   
               
               
                 5701 
                 gggttttcct ggtgtcccag gaggcacggg ccccaagggt gaccgtgggg agactggatc 
               
               
                   
               
               
                 5761 
                 caaaggggag cagggcctcc ctggagagcg tggcctgcga ggagagcctg gaagtgtgcc 
               
               
                   
               
               
                 5821 
                 gaatgtggat cggttgctgg aaactgctgg catcaaggca tctgccctgc gggagatcgt 
               
               
                   
               
               
                 5881 
                 ggagacctgg gatgagagct ctggtagctt cctgcctgtg cccgaacggc gtcgaggccc 
               
               
                   
               
               
                 5941 
                 caagggggac tcaggcgaac agggcccccc aggcaaggag ggccccatcg gctttcctgg 
               
               
                   
               
               
                 6001 
                 agaacgcggg ctgaagggcg accgtggaga ccctggccct caggggccac ctggtctggc 
               
               
                   
               
               
                 6061 
                 ccttggggag aggggccccc ccgggccttc cggccttgcc ggggagcctg gaaagcctgg 
               
               
                   
               
               
                 6121 
                 tattcccggg ctcccaggca gggctggggg tgtgggagag gcaggaaggc caggagagag 
               
               
                   
               
               
                 6181 
                 gggagaacgg ggagagaaag gagaacgtgg agaacagggc agagatggcc ctcctggact 
               
               
                   
               
               
                 6241 
                 ccctggaacc cctgggcccc ccggaccccc tggccccaag gtgtctgtgg atgagccagg 
               
               
                   
               
               
                 6301 
                 tcctggactc tctggagaac agggaccccc tggactcaag ggtgctaagg gggagccggg 
               
               
                   
               
               
                 6361 
                 cagcaatggt gaccaaggtc ccaaaggaga caggggtgtg ccaggcatca aaggagaccg 
               
               
                   
               
               
                 6421 
                 gggagagcct ggaccgaggg gtcaggacgg caacccgggt ctaccaggag agcgtggtat 
               
               
                   
               
               
                 6481 
                 ggctgggcct gaagggaagc cgggtctgca gggtccaaga ggcccccctg gcccagtggg 
               
               
                   
               
               
                 6541 
                 tggtcatgga gaccctggac cacctggtgc cccgggtctt gctggccctg caggacccca 
               
               
                   
               
               
                 6601 
                 aggaccttct ggcctgaagg gggagcctgg agagacagga cctccaggac ggggcctgac 
               
               
                   
               
               
                 6661 
                 tggacctact ggagctgtgg gacttcctgg accccccggc ccttcaggcc ttgtgggtcc 
               
               
                   
               
               
                 6721 
                 acaggggtct ccaggtttgc ctggacaagt gggggagaca gggaagccgg gagccccagg 
               
               
                   
               
               
                 6781 
                 tcgagatggt gccagtggaa aagatggaga cagagggagc cctggtgtgc cagggtcacc 
               
               
                   
               
               
                 6841 
                 aggtctgcct ggccctgtcg gacctaaagg agaacctggc cccacggggg cccctggaca 
               
               
                   
               
               
                 6901 
                 ggctgtggtc gggctccctg gagcaaaggg agagaaggga gcccctggag gccttgctgg 
               
               
                   
               
               
                 6961 
                 agacctggtg ggtgagccgg gagccaaagg tgaccgagga ctgccagggc cgcgaggcga 
               
               
                   
               
               
                 7021 
                 gaagggtgaa gctggccgtg caggggagcc cggagaccct ggggaagatg gtcagaaagg 
               
               
                   
               
               
                 7081 
                 ggctccagga cccaaaggtt tcaagggtga cccaggagtc ggggtcccgg gctcccctgg 
               
               
                   
               
               
                 7141 
                 gcctcctggc cctccaggtg tgaagggaga tctgggcctc cctggcctgc ccggtgctcc 
               
               
                   
               
               
                 7201 
                 tggtgttgtt gggttcccgg gtcagacagg ccctcgagga gagatgggtc agccaggccc 
               
               
                   
               
               
                 7261 
                 tagtggagag cggggtctgg caggcccccc agggagagaa ggaatcccag gacccctggg 
               
               
                   
               
               
                 7321 
                 gccacctgga ccaccggggt cagtgggacc acctggggcc tctggactca aaggagacaa 
               
               
                   
               
               
                 7381 
                 gggagaccct ggagtagggc tgcctgggcc ccgaggcgag cgtggggagc caggcatccg 
               
               
                   
               
               
                 7441 
                 gggtgaagat ggccgccccg gccaggaggg accccgagga ctcacggggc cccctggcag 
               
               
                   
               
               
                 7501 
                 caggggagag cgtggggaga agggtgatgt tgggagtgca ggactaaagg gtgacaaggg 
               
               
                   
               
               
                 7561 
                 agactcagct gtgatcctgg ggcctccagg cccacggggt gccaaggggg acatgggtga 
               
               
                   
               
               
                 7621 
                 acgagggcct cggggcttgg atggtgacaa aggacctcgg ggagacaatg gggaccctgg 
               
               
                   
               
               
                 7681 
                 tgacaagggc agcaagggag agcctggtga caagggctca gccgggttgc caggactgcg 
               
               
                   
               
               
                 7741 
                 tggactcctg ggaccccagg gtcaacctgg tgcagcaggg atccctggtg acccgggatc 
               
               
                   
               
               
                 7801 
                 cccaggaaag gatggagtgc ctggtatccg aggagaaaaa ggagatgttg gcttcatggg 
               
               
                   
               
               
                 7861 
                 tccccggggc ctcaagggtg aacggggagt gaagggagcc tgtggccttg atggagagaa 
               
               
                   
               
               
                 7921 
                 gggagacaag ggagaagctg gtcccccagg ccgccccggg ctggcaggac acaaaggaga 
               
               
                   
               
               
                 7981 
                 gatgggggag cctggtgtgc cgggccagtc gggggcccct ggcaaggagg gcctgatcgg 
               
               
                   
               
               
                 8041 
                 tcccaagggt gaccgaggct ttgacgggca gccaggcccc aagggtgacc agggcgagaa 
               
               
                   
               
               
                 8101 
                 aggggagcgg ggaaccccag gaattggggg cttcccaggc cccagtggaa atgatggctc 
               
               
                   
               
               
                 8161 
                 tgctggtccc ccagggccac ctggcagtgt tggtcccaga ggccccgaag gacttcaggg 
               
               
                   
               
               
                 8221 
                 ccagaagggt gagcgaggtc cccccggaga gagagtggtg ggggctcctg gggtccctgg 
               
               
                   
               
               
                 8281 
                 agctcctggc gagagagggg agcaggggcg gccagggcct gccggtcctc gaggcgagaa 
               
               
                   
               
               
                 8341 
                 gggagaagct gcactgacgg aggatgacat ccggggcttt gtgcgccaag agatgagtca 
               
               
                   
               
               
                 8401 
                 gcactgtgcc tgccagggcc agttcatcgc atctggatca cgacccctcc ctagttatgc 
               
               
                   
               
               
                 8461 
                 tgcagacact gccggctccc agctccatgc tgtgcctgtg ctccgcgtct ctcatgcaga 
               
               
                   
               
               
                 8521 
                 ggaggaagag cgggtacccc ctgaggatga tgagtactct gaatactccg agtattctgt 
               
               
                   
               
               
                 8581 
                 ggaggagtac caggaccctg aagctccttg ggatagtgat gacccctgtt ccctgccact 
               
               
                   
               
               
                 8641 
                 ggatgagggc tcctgcactg cctacaccct gcgctggtac catcgggctg tgacaggcag 
               
               
                   
               
               
                 8701 
                 cacagaggcc tgtcaccctt ttgtctatgg tggctgtgga gggaatgcca accgttttgg 
               
               
                   
               
               
                 8761 
                 gacccgtgag gcctgcgagc gccgctgccc accccgggtg gtccagagcc aggggacagg 
               
               
                   
               
               
                 8821 
                 tactgcccag gactgaggcc cagataatga gctgagattc agcatcccct ggaggagtcg 
               
               
                   
               
               
                 8881 
                 gggtctcagc agaaccccac tgtccctccc cttggtgcta gaggcttgtg tgcacgtgag 
               
               
                   
               
               
                 8941 
                 cgtgcgtgtg cacgtccgtt atttcagtga cttggtcccg tgggtctagc cttcccccct 
               
               
                   
               
               
                 9001 
                 gtggacaaac ccccattgtg gctcctgcca ccctggcaga tgactcactg tgggggggtg 
               
               
                   
               
               
                 9061 
                 gctgtgggca gtgagcggat gtgactggcg tctgacccgc cccttgaccc 
               
               
                   
               
            
           
           
               
               
            
               
                 NCBI Reference Sequence: NP_000085: 
                   
               
               
                 (SEQ ID NO: 2) 
                   
               
            
           
           
               
               
               
            
               
                    1 
                 mtlrllvaal cagilaeapr vraqhrervt ctrlyaadiv flldgsssig rsnfrevrsf 
                   
               
               
                   
               
               
                   61 
                 leglvlpfsg aasaqgvrfa tvqysddprt efgldalgsg gdvirairel sykggntrtg 
               
               
                   
               
               
                  121 
                 aailhvadhv flpqlarpgv pkvcilitdg ksqdlvdtaa qrlkgqgvkl favgiknadp 
               
               
                   
               
               
                  181 
                 eelkrvasqp tsdffffvnd fsilrtllpl vsrrvcttag gvpvtrppdd stsaprdlvl 
               
               
                   
               
               
                  241 
                 sepssgslry qwtaasgpvt gykvqytplt glgqplpser qevnvpaget svrlrglrpl 
               
               
                   
               
               
                  301 
                 teyqvtvial yansigeays gtarttaleg peltiqntta hsllvawrsv pgatgyrvtw 
               
               
                   
               
               
                  361 
                 rvlsggptqg gelgpgqgsv llrdlepgtd yevtvstlfg rsvgpatslm artdasveqt 
               
               
                   
               
               
                  421 
                 lrpvilgpts illswnlvpe argyrlewrr etgleppqkv vlpsdvtryq ldglqpgtey 
               
               
                   
               
               
                  481 
                 rltlytlleg hevatpatvv ptgpelpvsp vtdlqatelp gqrvrvswsp vpgatqyrii 
               
               
                   
               
               
                  541 
                 vrstqgvert lvlpgsqtaf dlddvgagls ytvrvsarvg pregsasvlt vrrepetpla 
               
               
                   
               
               
                  601 
                 vpglrvvvsd atrvrvawgp vpgasgfris wstgsgpess qtlppdstat ditglqpgtt 
               
               
                   
               
               
                  661 
                 yqvaysvlrg reegpaaviv artdplgpvr tvhvtqasss svtitwtrvp gatgyrvswh 
               
               
                   
               
               
                  721 
                 sahgpeksql vsgeatvael dglepdteyt vhvrahvagv dgppasvvvr tapepvgrvs 
               
               
                   
               
               
                  781 
                 rlqilnassd vlritwvgvt gatayrlawg rseggpmrhq ilpgntdsae irgleggvsy 
               
               
                   
               
               
                  841 
                 svrvtalvgd regtpvsivv ttppeappal gtlhvvqrge hslrlrwepv praggfllhw 
               
               
                   
               
               
                  901 
                 gpegggegsr vlgpelssyh ldglepatqy rvrlsvlgpa gegpsaevta rtesprvpsi 
               
               
                   
               
               
                  961 
                 elrvvdtsid svtlawtpvs rassyilswr plrgpgqevp gspqtlpgis ssqrvtglep 
               
               
                   
               
               
                 1021 
                 gvsyifsltp vldgvrgpea svtqtpvcpr gladvvflph atqdnahrae atrrvlerlv 
               
               
                   
               
               
                 1081 
                 lalgplgpqa vqvgllsysh rpsplfping shdlgiilqr irdmpymdps gnnlgtavvt 
               
               
                   
               
               
                 1141 
                 ahrymlapda pgrrqhvpgv mvllvdeplr gdifspirea gasglnvvml gmagadpeql 
               
               
                   
               
               
                 1201 
                 rrlapgmdsv qtffavddgp sldqaysgla talcgasftt qprpepcpvy cpkgqkgepg 
               
               
                   
               
               
                 1261 
                 emglrgqvgp pgdpglpgrt gapgpqgppg satakgergf pgadgrpgsp gragnpgtpg 
               
               
                   
               
               
                 1321 
                 apglkgspgl pgprgdpger gprgpkgepg apgqviggeg pglpgrkgdp gpsgppgprg 
               
               
                   
               
               
                 1381 
                 plgdpgprgp pglpgtamkg dkgdrgergp pgpgeggiap gepglpglpg spgpqgpvgp 
               
               
                   
               
               
                 1441 
                 pgkkgekgds edgapglpgq pgspgeqgpr gppgaigpkg drgfpgplge agekgergpp 
               
               
                   
               
               
                 1501 
                 gpagsrglpg vagrpgakgp egppgptgrq gekgepgrpg dpavvgpava gpkgekgdvg 
               
               
                   
               
               
                 1561 
                 pagprgatgv qgergppglv lpgdpgpkgd pgdrgpiglt gragppgdsg ppgekgdpgr 
               
               
                   
               
               
                 1621 
                 pgppgpvgpr grdgevgekg degppgdpgl pgkagerglr gapgvrgpvg ekgdqgdpge 
               
               
                   
               
               
                 1681 
                 dgrngspgss gpkgdrgepg ppgppgrlvd tgpgarekge pgdrgqegpr gpkgdpglpg 
               
               
                   
               
               
                 1741 
                 apgergiegf rgppgpqgdp gvrgpagekg drgppgldgr sgldgkpgaa gpsgpngaag 
               
               
                   
               
               
                 1801 
                 kagdpgrdgl pglrgegglp gpsgppglpg kpgedgkpgl ngkngepgdp gedgrkgekg 
               
               
                   
               
               
                 1861 
                 dsgasgregr dgpkgergap gilgpqgppg lpgpvgppgq gfpgvpggtg pkgdrgetgs 
               
               
                   
               
               
                 1921 
                 kgeqglpger glrgepgsvp nvdrlletag ikasalreiv etwdessgsf lpvperrrgp 
               
               
                   
               
               
                 1981 
                 kgdsgeqgpp gkegpigfpg erglkgdrgd pgpqgppgla lgergppgps glagepgkpg 
               
               
                   
               
               
                 2041 
                 ipglpgragg vgeagrpger gergekgerg eggrdgppgl pgtpgppgpp gpkvsvdepg 
               
               
                   
               
               
                 2101 
                 pglsgeggpp glkgakgepg sngdqgpkgd rgvpgikgdr gepgprgqdg npglpgergm 
               
               
                   
               
               
                 2161 
                 agpegkpglq gprgppgpvg ghgdpgppga pglagpagpq gpsglkgepg etgppgrglt 
               
               
                   
               
               
                 2221 
                 gptgavglpg ppgpsglvgp qgspglpgqv getgkpgapg rdgasgkdgd rgspgvpgsp 
               
               
                   
               
               
                 2281 
                 glpgpvgpkg epgptgapgq avvglpgakg ekgapgglag dlvgepgakg drglpgprge 
               
               
                   
               
               
                 2341 
                 kgeagragep gdpgedgqkg apgpkgfkgd pgvgvpgspg ppgppgvkgd lglpglpgap 
               
               
                   
               
               
                 2401 
                 gvvgfpgqtg prgemgqpgp sgerglagpp gregipgplg ppgppgsvgp pgasglkgdk 
               
               
                   
               
               
                 2461 
                 gdpgvglpgp rgergepgir gedgrpgqeg prgltgppgs rgergekgdv gsaglkgdkg 
               
               
                   
               
               
                 2521 
                 dsavilgppg prgakgdmge rgprgldgdk gprgdngdpg dkgskgepgd kgsaglpglr 
               
               
                   
               
               
                 2581 
                 gllgpqgqpg aagipgdpgs pgkdgvpgir gekgdvgfmg prglkgergv kgacgldgek 
               
               
                   
               
               
                 2641 
                 gdkgeagppg rpglaghkge mgepgvpgqs gapgkeglig pkgdrgfdgq pgpkgdqgek 
               
               
                   
               
               
                 2701 
                 gergtpgigg fpgpsgndgs agppgppgsv gprgpeglqg qkgergppge rvvgapgvpg 
               
               
                   
               
               
                 2761 
                 apgergeqgr pgpagprgek geaalteddi rgfvrqemsq hcacqgqfia sgsrplpsya 
               
               
                   
               
               
                 2821 
                 adtagsqlha vpvlrvshae eeervppedd eyseyseysv eeyqdpeapw dsddpcslpl 
               
               
                   
               
               
                 2881 
                 degsctaytl rwyhravtgs teachpfvyg gcggnanrfg treacerrcp prvvqsqgtg 
               
               
                   
               
               
                 2941 
                 taqd 
               
            
           
         
       
     
     Age Related Disorders 
     The disclosure features the treatment of age related disorders. Age related disorders can include but are not limited to, cancer, e.g., skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo malignnt melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma; vaginal tearing; chronic or non-healing wounds, dermatoheliosis, wrinkles, lentigod, beborrheic keratoses, diabetes, cardiovascular disease, or nutritional deficiency. 
     Indications 
     The disclosure features a pharmaceutical composition comprising collagen 7, or functional fragment or variant thereof, and one or more pharmaceutically acceptable carriers, for use in treating an age related disorder described herein. The disclosure features a pharmaceutical composition comprising collagen 7, or functional fragment or variant thereof, e.g., described herein, and one or more pharmaceutically acceptable carriers for use in preventing, preventing the progression of, or delaying the onset of one or more symptom associated an age related disorder described herein. 
     Subject Selection 
     Subjects who may benefit from the use of the methods described herein include, but are not limited to, subjects diagnosed with an age related disorder e.g., skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma; vaginal tearing; chronic or non-healing wounds. In addition, or alternatively, the subject may have, or may be at risk of developing, an age related disorder e.g., skin cancer, e.g., squamous cell carcinoma; melanoma, e.g., superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma; basal cell carcinoma; or Kaposi&#39;s sarcoma; vaginal tearing; chronic or non-healing wounds. 
     Organ Transplant Recipients 
     The disclosure features the treatment of subjects who have received an organ transplant. The organ transplant can be a solid organ transplant e.g., heart, liver, kidney, lung, pancreas, intestine, stomach, testis, etc as contrasted to liquid transplanted tissues, e.g., bone marrow, pancreatic islets, etc. 
     Indications 
     The disclosure features a pharmaceutical composition comprising collagen 7, or functional fragment or variant thereof, and one or more pharmaceutically acceptable carriers, for use in treating a subject who has received an organ transplant as described herein. The disclosure features a pharmaceutical composition comprising collagen 7, or functional fragment or variant thereof, e.g., described herein, and one or more pharmaceutically acceptable carriers for use in preventing, preventing the progression of, or delaying the onset of one or more symptoms associated with receiving an organ transplant as described herein. 
     Subject Selection 
     Subjects who may benefit from the use of the methods described herein include, but are not limited to, subjects who have received an organ transplant. In addition, or alternatively, the subject may have, or may be at risk of developing, a disorder in which the treatment of the disorder is an organ transplant, e.g., cancer of a solid organ, e.g., liver cancer, lung cancer, pancreatic cancer; kidney cancer, testicular cancer, intestinal cancer, stomach cancer, heart cancer; failure of a solid organ, e.g., kidney failure, heart failure, liver failure, lung failure, pancreatic failure; or diagnosed with a disorder which would lead to failure of a solid organ, e.g., chronic renal failure; acute renal failure; type 1 diabetes; type 2 diabetes; chronic kidney disease; immune system conditions, e.g., lupus, chronic viral illnesses, e.g., HIV/AIDS, hepatitis B, hepatitis C; urine blockage in the kidneys; kidney damage; impaired blood flow to the kidneys; congestive heart failure; coronary artery disease; high blood pressure; faulty heart valves; cardiomyopathy; myocarditis; heart arrhythmias; acute heart failure; chronic heart failure; liver failure; liver cirrhosis; biliary duct atresia; cystic fibrosis; early stage liver cancer; primary biliary cirrhosis; primary sclerosing cholangitis; Wilson&#39;s disease; lung cancer. 
     Preparation of Collagen 7 and Functional Fragments and Variants Thereof 
     Collagen 7 and functional fragments and variants thereof can be synthesized by standard molecular biology techniques in standard cell lines, e.g., CHO, HEK293, fibroblast or keratinocyte cells. Standard cell culture procedures and conditions may be used for culture of host cells described herein and are known to those skilled in the art. Host cells cultured for expression of recombinant collagen 7, such as HEK293 cells, may be cultured in routinely used cell culture media (e.g. Dulbecco&#39;s modified Eagle&#39;s medium (DMEM)/Ham&#39;s F-12 (1:1) with suitable supplementation of serum, antibiotics, etc, dependent on the application) as referenced in, ((Chen et al.  J Bio Chem  277(18): 2118-2124 (2002)), (Chen et al.  J Bio Chem  275: 32(11): 24429-24435 (2000)), (Chen et al.  J Bio Chem  276(24): 21649-21655 (2001)). 
     Host cells may be engineered to express other proteins to optimize production of the recombinant collagen 7. This may include, but not limited to, the co-expression of the processing enzymes prolyl hydroxylase, prolidase, or glycosyl-transferase, by exogenously introducing isolated nucleic acid or recombinant expression vectors encoding the appropriate nucleic acid sequence, in host cells comprising collagen 7 nucleic acid sequence or recombinant expression vector. The triple helical assembly of collagen 7 often requires hydroxylation and the presence of ascorbic acid in the host cell growth media. As demonstrated in the reference, (Chen et al.  J Bio Chem  277 (18): 2118-2124 (2002)), recombinant type 7 collagen produced, recovered, and purified from HEK293 cells in the presence of ascorbic acid was secreted as an approximately 900-kDa protein, corresponding to the association of three type 7 collagen monomers (each monomer 290-kDa). Ascorbic acid may be used in the host cell culture conditions to aid in proper processing of the recombinant protein. 
     Suitable vectors for use herein are those that can express collagen 7, prolyl hydroxylase, prolidase, or glycosyl-transferase, or a functional portion thereof. In order to express the proteins described herein, the nucleotide sequence encoding the appropriate protein, or a functional equivalent, can be inserted into a suitable vector. A suitable vector contains the necessary and appropriate transcriptional and translational control sequences for expression of the inserted nucleic acid sequence. Standard methods, known to those skilled in the art, may be used to construct the recombinant expression vectors containing the nucleic acid sequences described herein. These methods include, but are not limited to, in vitro recombinant techniques, synthetic techniques, and in vivo recombination/genetic recombination; the choice of method depends on the nature of the specific nucleotide fragments and may be determined by persons skilled in the art. 
     Suitable vectors for use herein may contain an origin of replication and a restriction endonuclease sequence site. Persons skilled in the art would have knowledge of suitable origin of replication and restriction endonuclease sequences for use in the host cell. Suitable vectors for use herein may contain sequence elements to aid transcription, including, but not limited to, promoter and enhancer elements. Persons skilled in the art would have knowledge of various transcriptional control elements, including but not limited to, promoters, inducible promoters, and enhancer elements, that would be suitable in the host cell. Suitable vectors for use herein may also contain a selectable marker gene that encodes a product necessary for the host cell to grow and survive under specific conditions, aiding in the selection of host cells into which the vector has been introduced. Typical selection genes may include, but are not limited to, genes encoding a protein that confers resistance to an antibiotic, drug, or toxin (e.g., tetracycline, ampicilin, neomycin, hygromycin, etc). Persons skilled in the art would have knowledge of coding sequences for suitable selectable markers and reporter genes for use in the host cell. 
     Expression vectors described herein can be introduced into host cells via conventional transformation or transfection techniques. Transformation and transfection techniques include, but are not limited to, calcium phosphate or calcium chloride coprecipitation, DEAE-dextran-mediated transfection, lipofectamine, electroporation, microinjection, and viral mediated transfection (as referenced in U.S. Pat. No. 6,632,637 (McGrew)). Persons skilled in the art would have knowledge of suitable transformation and transfection methods based on the host cell/vector combination. For long term, high yield production of recombinant proteins, stable expression of the recombinant protein may be preferred. Host cells that stably express the recombinant protein may be engineered. 
     The recombinant expression vectors described herein may be introduced into a suitable host cell, which may include a living cell capable of expressing the protein coding region from the defined recombinant expression vector. The term “host cell” refers not only to the particular subject cell but to the progeny or potential progeny of the particular subject cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. Various host cell expression systems may be utilized to express the nucleic acid molecules described herein. These include, but are not limited to yeast or fungi, transformed with recombinant yeast or fungi expression vectors containing the appropriate nucleic acid sequence; insect cell systems infected with recombinant virus expression vectors or transformed with recombinant plasmid expression vectors containing the appropriate nucleic acid sequence; or mammalian cell systems (e.g., primate cell, human cell, rodent cell, etc) transfected with expression vectors containing the appropriate nucleic acid sequence. Suitable host cells may include primary or transformed cell lines, including, but not limited to, fibroblasts, CHO, HEK293, C127, VERO, BHK, HeLa, COS, MDCK, etc (as referenced in U.S. Pat. No. 6,632,637 (McGrew)). Other suitable host cells are known to those skilled in the art. 
     Modifications, including, but not limited to, glycosylation, phosphyorylation and processing of protein products may be important to the function of a protein. Different host cells have various characteristics and mechanisms for post-translational processing and modification of proteins. A host cell that is capable of modulating expression of the nucleic acid sequences contained in the vector, or modulating expression of the vector nucleic acid sequences, or modifying and processing the gene product encoded in the vector sequence in a specific manner may be chosen. Mammalian host cells may be chosen to ensure the correct modification and processing of the recombinant protein. Such mammalian host cells may include, but are not limited to, CHO, HEK293, human fibroblasts, and human keratinocytes. 
     Proteins produced by recombinant methods described herein may be recovered from the host cell culture system according to standard protocols known in the art (e.g., precipitation, centrifugation, etc). Recombinant collagen 7 described herein may be secreted into the host cell medium and recovered by ammonium sulfate precipitation and subsequent centrifugation; as demonstrated in the following reference, (Chen et al.  J Bio Chem  277(18): 2118-2124 (2002)). Proteins produced and recovered by recombinant and molecular biology methods described herein, may be purified according to standard protocols known in the art (e.g., dialysis, ion exchange chromatography, affinity chromatography, SDS gel electrophoresis, etc). The recombinant collagen 7 described herein may be purified to homogeneity by ion exchange chromatography; as demonstrated in the following reference, (Chen et al.  J Bio Chem  277(18): 2118-2124 (2002)). 
     Optionally collagen 7 may be further purified. Purification may be achieved using any method known in the art, including, but not limited to affinity chromatography, e.g., an anti-collagen 7 antibody column; hydrophobic interaction chromatography; ion exchange chromatography; size exclusion chromatography; electrophoretic procedures, e.g., isoelectric focusing, differential solubility (e.g., ammonium sulfate precipitation), or extraction, and the like. 
     Compositions 
     The disclosure provides a pharmaceutical composition comprising collagen 7 or functional fragment or variant thereof. Pharmaceutical compositions may take the form of any acceptable pharmaceutical formulation. Pharmaceutical compositions can be formulated in a variety of different forms, such as liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form can depend on the intended mode of administration and therapeutic application. 
     Exemplary pharmaceutical compositions are described below. The pharmaceutical compositions include those suitable for parenteral (including intravenous, subcutaneous, intradermal, intramuscular, and intraarticular), topical (including dermal, transdermal, transmucosal, buccal, sublingual, and intraocular), and rectal administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient. 
     Compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The composition may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as EDTA, mannitol, 1,3-butanediol, water, Ringer&#39;s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents. The compositions may contain pharmaceutically acceptable substances or adjuvants, including, but not limited to, EDTA, e.g., 0.5 mM EDTA; pH adjusting and buffering agents and/or tonicity adjusting agents, e.g., sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate; minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents or preservatives. 
     It should be understood that in addition to the ingredients particularly mentioned above, the composition may include other agents conventional in the art having regard to the type of formulation in question. 
     Administration 
     In practicing the methods described herein, collagen 7 or functional fragment or variant thereof may be administered as a single dose. Collagen 7 or functional fragment or variant thereof may be administered as multiple subsequent doses. 
     In practicing the methods described herein, collagen 7 or functional fragment or variant thereof may be chronically administered. Chronic administration can include the administration of more than one dose of an agent over a period of time. Chronic administration can include regular administration for an extended period of time. Chronic administration can include the administration of therapy over a prolonged period of time, in some cases, for the duration of a subject&#39;s lifetime, so that the concentration of the therapeutic agent is maintained at a therapeutically or prophylactically effective level throughout the course of treatment. 
     The period of time of chronic administration can be for the lifetime of the subject. The period of time of chronic administration can include, but is not limited to, at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 25 years, at least 30 years, at least 35 years, at least 40 years, at least 45 years, at least 50 years, at least 100 years, at least 150 years, or anytime period between 3 months and 150 years. 
     Chronic administration can include a series of doses which together provide an effective amount for treating and/or preventing, preventing the progression of, or delaying the onset of symptoms associated with a disorder described herein. A pharmaceutical composition comprising collagen 7 or functional fragment or variant thereof may be administered on various dosing schedules. The dosing schedule can be dependent on several factors including, the severity of the disorder described herein; the specific composition of collagen 7 or functional fragment or variant thereof employed for treatment; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific collagen 7 or functional fragment or variant thereof composition employed; and like factors well known in the medical arts. 
     Exemplary dosing schedules of collagen 7 or functional fragment or variant thereof include, once daily, or once weekly, or once every other week, or once monthly, or once every other month, or once every three months, or once every 6 months, or once every 12 months, or once every 18 months, or once every 24 months. The composition can be administered twice per week or twice per month, or once every two, three or four weeks. The composition can be administered as two, three, or more sub-doses at appropriate intervals or even using continuous infusion or delivery through a controlled release formulation. In that case, the therapeutic agent contained in each sub-dose may be correspondingly smaller in order to achieve the total daily dosage. The dosage can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation, which provides sustained release of the agent over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site. The total daily, weekly, or monthly usage of collagen 7 composition can be decided by an attending physician within the scope of sound medical judgment. 
     The present disclosure features methods including, administering a treatment comprising collagen 7 or functional fragment or variant thereof. The disclosure can further include selecting a regimen, e.g., dosage, formulation, route of administration, number of dosages, or adjunctive or combination treatments of collagen 7 or functional fragment or variant thereof. The disclosure can further include the administration of the selected regimen. 
     A treatment comprising collagen 7 or functional fragment or variant thereof disclosed herein, may be administered by any route, including by those routes currently accepted and approved for known products. Exemplary routes of administration include, e.g., topical (e.g. by powders, ointments, creams, gels, lotions, and/or drops) or systemic (e.g., intravenous). 
     Even upon improvement of a patient&#39;s condition, chronic administration of collagen 7 or functional fragment or variant thereof may be administered. The dosage or frequency of administration, or both, may not be reduced, as a function of disease symptoms. The dosage or frequency of administration, or both, may be reduced, as a function of disease symptoms, to a level at which the improved condition is retained. Subjects may require intermittent changes in dosage or frequency of administration of treatment on a long-term basis upon any recurrence of disease symptoms. 
     Combination Treatments 
     The present disclosure encompasses combined administration of an additional agent or agents with collagen 7 or functional fragments and variants thereof. Additional agents may include, but are not limited to, chemotherapeutic agents, immunosuppressants, antibiotics, analgesics, opioids, anti-virals, or anti-inflammatory agents. Combination therapy can also include but is not limited to surgery, e.g., Mohs surgery, cryosurgery, curettage, electrodissection, laser surgery, demabrasion, excision, e.g., simple excision, shave excision; photodynamic therapy; radiation therapy; chemotherapy; biologic therapy, e.g. interferon and imiquimod. 
     Additional agents disclosed herein, may be administered by any route, including by those routes currently accepted and approved for known products. Exemplary routes of administration include, e.g., topical (e.g. by powders, ointments, creams, gels, lotions, and/or drops) and systemic (e.g., intravenous). 
     Chemotherapeutic Agents 
     Chemotherapeutic agents can be administered systemically, e.g., intravenously, or topically, e.g., in the form of a cream, lotion, or ointment, e.g., in the form of a cream, lotion, or ointment applied to the skin or skin lesion. 
     Chemotherapeutic agents can include but are not limited to, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, toposimerase inhibitors and others). Exemplary agents include aclarubicin, actinomycin, alitretinon, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, endamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucid, etoposide, floxuridine, fludarabine, fluorouracil (5fu), fotemustine, gemcitabine, gliadel implants, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene ceradenovec, strataplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurine, tioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zorubicin, and other cytostatic or cytotoxic agents described herein. Additional exemplary chemotherapeutic agents, include 5-fluorouracil (5fu), adrucil (fluorouracil), aldara (imiquimod), efudex (fluorouracil), erivedge (vismodegib), fluoroplex (fluorouracil), fluorouracil, imiquimod, vismodegib, aldesleukin, dacarbazine, dtic-dome (dacarbazine), ipilimumab, proleukin (aldesleukin), vemurafenib, yervoy (ipilimumab), zelboraf (vemurafenib), retinoids. 
     Targeted Therapy 
     Collagen 7 or functional fragments and variants thereof described herein, can be administered with a targeted cancer therapy. Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. An exemplary targeted therapy includes vismodegib (erivedge). Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, desatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and also cyclin-depdendent kinase inhibitors such as alvocidib and seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, ranibizumab. exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, the targeted therapy can be used in combination with Collagen 7 or functional fragments and variants thereof described herein. 
     Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®. 
     Immunotherapy 
     Collagen 7 or functional fragments and variants thereof described herein, can be administered with an immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patient&#39;s own immune system to fight the tumor. Contemporary methods for generating an immune response against tumors include intravesicular Bacille Calmette-Guerin (BCG) vaccine immunotherapy, and use of interferons and other cytokines to induce an immune response. Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor&#39;s immune cells will often attack the tumor in a graft-versus-tumor effect. In some embodiments, the immunotherapy agents can be used in combination with Collagen 7 or functional fragments and variants thereof described herein. Exemplary immunotherapy includes injections of BCG vaccine, interleukin-2, interferon, ipilimumab (Yervoy); vemurafenib (Zelboraf). 
     Hormonal Therapy 
     Collagen 7 or functional fragments and variants thereof described herein, can be administered with a hormonal therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. The hormonal therapy agents can be used in combination with Collagen 7 or functional fragments and variants thereof described herein. 
     Anti-Inflammatory Agents 
     Collagen 7 or functional fragments and variants thereof described herein, can be administered with an anti-inflammatory agent. Anti-inflammatory agents can include, but are not limited to, non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamates)(mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective cox-2 inhibitors (coxibs) (celecoxib), sulphonanilides (nimesulide). Steroids (e.g. hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone). 
     Analgesic Agents 
     Analgesics can include but are not limited to, opiates (e.g. morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetomal and Non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamates)(mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective cox-2 inhibitors (coxibs) (celecoxib), sulphonanilides (nimesulide). 
     Antiemetic Agents 
     Collagen 7 or functional fragments and variants thereof described herein, can be administered with an antiemetic agent. Antiemetic agents can include, but are not limited to, 5-HT3 receptor antagonists (dolasetron (anzemet), granisetron (kytril, sancuso), ondansetron (zofran), tropisetron (navoban), palonosetron (aloxi), mirtazapine (remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (reglan), alizapride, prochlorperazine (compazine, stemzine, buccastem, stemetil, phenotil), NK1 receptor antagonist (aprepitant (emend), antihistamines (cyclizine, diphenhydramine (benadryl), dimenhydrinate (gravol, dramamine), meclozine (bonine, antivert), promethazine (pentazine, phenergan, promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyoscine), steroids (dexamethasone). 
     Immunosuppressants 
     Immunosuppressants can include but are not limited to cyclosporine A (CyA, neoral, gengraf, sangcya, sandimmune); prograf (tacrolimus); imuran (azathioprine); steroids, e.g., prednisone, deltasone, methylprednisolone; or rapamune (sirolimus). 
     Antibiotics 
     Antibiotics can include, but are not limited to, aknilox, ambisome, amoxycillin, ampicillin, augmentin, avelox, azithromycin, bactroban, betadine, betnovate, blephamide, cancidas, cefaclor, cefadroxil, cefdinir, cefepime, cefix, cefixime, cefoxitin, cefpodoxime, cefprozil, cefuroxime, cefzil, cephalexin, cephazolin, ceptaz, chloramphenicol, chlorhexidine, chloromycetin, chlorsig, ciprofloxacin, clarithromycin, clindagel, clindamycin, clindatech, cloxacillin, colistin, co-trimoxazole, demeclocycline, diclocil, dicloxacillin, doxycycline, duricef, erythromycin, flagyl alcohol, flagyl dosage, flagyl pregnancy, flagyl side effects, flagyl treatment, flamazine, floxin, framycetin, fucidin, furadantin, fusidic, gatifloxacin, gemifloxacin, gemifloxacin, ilosone, iodine, levaquin, levofloxacin, loceryl, lomefloxacin, maxaquin, mefoxin, meronem, minocycline, moxifloxacin, myambutol, mycostatin neosporin, netromycin, nitrofurantoin, norfloxacin, norilet, ofloxacin, omnicef, ospamox, oxytetracycline, paraxin, penicillin, pneumovax, polyfax, povidone, rifadin, rifampin, rifaximin, rifinah, rimactane, rocephin, roxithromycin, seromycin, soframycin, sparfloxacin, staphlex, targocid, tetracycline, tetradox, tetralysal, tobramycin, tobramycin, trecator, tygacil, vancocin, velosef, vibramycin, xifaxan, zagam, zitrotek, zoderm, zymar, and zyvox. 
     Anti-Viral Agents 
     Anti-viral agents can include, but are not limited to, abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type iii, interferon type ii, interferon type i, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconarilpodophyllotoxin, protease inhibitor, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, stavudine, tea tree oil, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine. 
     When collagen 7 or functional fragment or variant thereof is administered in combination with an additional agent or a plurality of agents, the dosage of collagen 7 or functional fragment or variant thereof may on its own comprise an effective amount and an additional agent or agents may further augment the therapeutic benefit to the patient. Alternatively the combination of collagen 7 or functional fragment or variant thereof and a second agent may together comprise an effective amount for treating and/or preventing, preventing a disorder described herein. The effective amounts may be defined in the context of particular treatment regimens, including, e.g., timing and number of administrations, modes of administrations, formulations, etc.