COMPOSITIONS AND METHODS FOR INHIBITING FACTOR D
The application discloses methods and compositions for the inhibition of the alternative complement pathway. The methods and compositions involve the use of aptamers for inhibiting complement Factor D. The application further provides anti-Factor D aptamers for the treatment of dry age-related macular degeneration, geographic atrophy, wet age-related macular degeneration or Stargardt disease.
1 .- 18 . (canceled)
19 . A method comprising: administering to a subject in need thereof a therapeutically effective amount of an aptamer that selectively blocks a catalytic cleft of complement Factor D.
20 . The method of claim 19 , wherein said aptamer inhibits a function associated with complement Factor D.
21 .- 24 . (canceled)
25 . The method of claim 19 , wherein said aptamer is an RNA aptamer or modified RNA aptamer.
26 . The method of claim 19 , wherein said aptamer inhibits a function of said complement Factor D with an IC 50 of about 50 nM or less as measured by an alternative complement-dependent hemolysis assay.
27 .- 29 . (canceled)
30 . The method of claim 19 , wherein said aptamer inhibits activity of complement Factor D as measured by a Factor D esterase activity assay as compared to a control.
31 . The method of claim 19 , wherein said aptamer inhibits activity of complement Factor D as measured by a hemolysis assay.
32 . The method of claim 19 , wherein said aptamer selectively binds to said catalytic cleft of complement Factor D with a K d of less than about 50 nM.
33 .- 66 . (canceled)
67 . The method of claim 19 , wherein said subject in need thereof has or is suspected of having an ocular disease or disorder.
68 . The method of claim 67 , wherein said ocular disease or disorder is selected from the group consisting of: dry age-related macular degeneration, wet age-related macular degeneration, geographic atrophy, and Stargardt disease.
69 . The method of claim 67 , wherein said therapeutically effective amount is an amount effective to treat said ocular disease or disorder, or an amount effective to ameliorate a symptom associated therewith.
70 . The method of claim 19 , wherein said administering further comprises administering said therapeutically effective amount of said aptamer to said subject by intravitreal administration.
71 . The method of claim 19 , wherein said administering further comprises administering said therapeutically effective amount of said aptamer to said subject in need thereof at least once every 8 weeks.
72 . The method of claim 19 , wherein said administering further comprises administering to said subject in need thereof a pharmaceutical composition comprising said therapeutically effective amount of said aptamer.
73 . The method of claim 19 , wherein said subject in need thereof is a human.
74 . The method of claim 73 , wherein said human is greater than 50 years old.
75 . The method of claim 73 , wherein said human is from 6-20 years old.
76 . The method of claim 19 , wherein said subject in need thereof has one or more mutations in complement factor H, complement component 3, complement component 2, complement factor B, complement factor I, ABC4A, ELOVL4, or any combination thereof.
77 . The method of claim 19 , wherein said aptamer is conjugated to a polyethylene glycol (PEG) polymer.
78 . The method of claim 19 , wherein said aptamer comprises one or more modified nucleotides.
79 . The method of claim 19 , wherein said aptamer has an intravitreal half-life of at least 6 days in a human, an intravitreal half-life of at least 2 days in a rabbit, an intravitreal half-life of at least 3 days in a primate, or any combination thereof.
80 . The method of claim 19 , wherein said therapeutically effective amount is from about 0.01 mg to about 150 mg of said aptamer in about from 25 μl to about 100 μl volume per eye.