Methods for inhibiting complement activation and uses thereof

Abstract

The present invention provides methods for inhibiting complement activation and uses thereof. More specifically, the present invention provides methods for inhibiting complement activation using inorganic polyphosphates of at least 10 phosphate units. The polyphosphates inhibit complement activation by one or more of: binding to the C6 complement protein, C1-esterase inhibitor (C1-inh), factor H or factor B; enhancing the activity of C1-inh; interfering with C1s-mediated cleavage of C2; destabilizing the C5b-6 complement protein complex; interfering with C5b,6 interaction with C7; interfering with binding of C5b-7 to a cell membrane; interfering with integration of C5b-7 into a cell membrane; interfering with binding of C5b-8 to a cell membrane; interfering with integration of C5b-8 into a cell membrane; destabilizing the membrane attack complex (MAC); or reducing the amount of C5b-9 deposited on a cell surface.

1 . A method for treating a complement-associated disorder, the method comprising administering an effective amount of a polyphosphate to a subject in need thereof, wherein the polyphosphate comprises at least 10 phosphate units. 
     
     
         2 . The method of  claim 1  wherein the complement-associated disorder is a complement-associated eye disorder, a complement-associated inflammatory disorder, a complement-associated immune disorder, a complement-associated central nervous system disorder, a complement-associated vascular disorder, a complement-associated ischemic disorder, a complement-associated lung disorder, a complement-mediated tissue injury, a complement-associated infection, a complement-associated cancer, an alternative pathway-associated disorder, a lectin pathway-associated disorder, a classical pathway-associated disorder, or a combination thereof. 
     
     
         3 . The method of  claim 1  wherein the complement-associated disorder is age-related macular degeneration or rheumatoid arthritis. 
     
     
         4 . The method of  claim 3  wherein the is age-related macular degeneration is dry age-related macular degeneration. 
     
     
         5 . The method of  claim 1  wherein the administering is by parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, intravitreal, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, epidermal, sub-epidermal, dermal, sub-dermal, aerosol, systemic, topical, injection, inhalation, lavage, or oral administration. 
     
     
         6 . The method of  claim 1  wherein the polyphosphate is administered locally to the site of the complement-associated disorder. 
     
     
         7 . The method of  claim 1  wherein the method comprises ameliorating one or more symptoms associated with the complement-associated disorder. 
     
     
         8 . The method of  claim 1  wherein the polyphosphate comprises between about 10 to about 10,000 phosphate units. 
     
     
         9 . The method of  claim 1  wherein the polyphosphate is administered to achieve a concentration of about 10 μM to about 10000 μM. 
     
     
         10 . The method of  claim 1  wherein the polyphosphate is administered in an amount effective to substantially reduce hemolytic activity. 
     
     
         11 . The method of  claim 1  wherein the subject is a human. 
     
     
         12 .- 19 . (canceled) 
     
     
         20 . A method for diagnosing a complement-associated disorder in a subject, the method comprising determining the level of complement activation in the presence or absence of a polyphosphate in a sample obtained from said subject, wherein the polyphosphate comprises at least 10 phosphate units, and wherein a decrease in the level of complement activation in the presence of the polyphosphate is indicative of a complement-associated disorder.