Treatment of diseases related to hyperactivity of the complement system
Rising the level of Factor I above physiological levels can be used to treat diseases in which the underlying pathology is linked to overactivity of the C3b-feedback cycle and the generation and pro-inflammatory effects of iC3b. Methods, agents, and compositions for treatment of such diseases are described.
1. A method for treating Age-related Macular Degeneration (AMD) or atypical haemolytic uraemic syndrome (aHUS) in a subject in need thereof, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of an agent selected from native Factor I and a polypeptide that has at least 90% amino acid identity with native Factor I and that retains C3b-inactivating and iC3b-degradation activity, and does not comprise Factor H, to the subject, and wherein the therapeutically effective amount of the agent increases the level of C3b-inactivating and iC3b-degradation activity in the plasma of the subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity, thereby treating the AMD or aHUS in the subject.
2. The method of claim 1 , wherein the agent is administered at a dosage of from 6.5 mg to 250 mg.
3. A method according to claim 1 , wherein the subject has a normal level of C3b-inactivating and iC3b-degradation activity provided by the subject's Factor I.
4. A method according to claim 3 , wherein the normal level is in the range 30-40 μg/ml Factor I in the subject's plasma.
5. A method according to claim 1 , wherein the level of activity in the subject's plasma is increased by at least 10% above the normal level.
6. A method according claim 1 , wherein the level of activity in the subject's plasma is increased by no more than 50%.
7. A method according to claim 1 , wherein the level of activity is increased by intravenous or intramuscular administration of 0.05 to 20 mg/kg of the agent to the subject.
8. A method according to claim 1 , wherein the level of activity is increased by intraocular administration of 0.001 to 1 mg/eye Factor I to the subject.
9. A method according to claim 1 , wherein the agent is administered at a dosage of from 6.5 mg to less than 50 mg.
10. A method according to claim 1 , further comprising determining whether the subject has a genetic predisposition to the disease or a family history of the disease, and administering appropriate therapy depending on the result of the determination.
11. A method according to claim 10 , wherein the genetic predisposition is selected from the group consisting of: a mutation in Factor H that reduces its ability to function as a Factor I cofactor compared with wild-type Factor H; a mutation in Factor H that reduces its binding to C3b compared with wild-type Factor H; homozygous Factor H deficiency; a mutation in membrane cofactor protein (MCP) that reduces its function compared with wildtype MCP; heterozygous Factor I deficiency; a gain-of-function mutation in Factor B; and a C3F allotype.
12. A method according to claim 1 , wherein the subject is a human subject or a domestic pet.
13. The method of claim 1 wherein the subject is a human subject.
14. The method of claim 13 wherein the method comprises administering native Factor I.
15. The method of claim 13 wherein the human subject is suffering from Age-related Macular Degeneration.
16. The method of claim 13 wherein the human subject is suffering from atypical haemolytic uraemic syndrome (aHUS).
17. The method of claim 1 wherein the native Factor I is recombinant.
18. The method of claim 1 wherein the pharmaceutical composition contains from 6.5 mg to 250 mg of native Factor I.
19. A method for treating Age-related Macular Degeneration (AMD) or atypical haemolytic uraemic syndrome (aHUS) in a subject in need thereof, which comprises administering by intravenous, intraperitoneal, intramuscular, or intradermal administration a therapeutically effective amount of an agent selected from native Factor I, and a polypeptide that has at least 90% amino acid identity with native Factor I and that retains C3b-inactivating and iC3b-degradation activity, to the subject, wherein the agent is administered in the absence of Factor H, and wherein the therapeutically effective amount of the agent increases the level of C3b-inactivating and iC3b-degradation activity in the plasma of the subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity, thereby treating the AMD or aHUS in the subject.
20. A method for treating Age-related Macular Degeneration (AMD) or atypical haemolytic uraemic syndrome (aHUS) in a subject in need thereof, which comprises administering a therapeutically effective amount of an agent selected from native Factor I, and a polypeptide that has at least 90% amino acid identity with native Factor I and that retains C3b-inactivating and iC3b-degradation activity, to the subject, wherein the agent is administered in the absence of Factor H, and wherein the therapeutically effective amount of the agent increases the level of C3b-inactivating and iC3b-degradation activity in the subject's plasma to a level that exceeds a normal plasma level of C3b-inactivating and iC3b-degradation activity, thereby treating the AMD or aHUS in the subject.