Modulating permeability of the blood cerebrospinal fluid barrier
The present invention relates to methods and compositions for modulating the blood CSF barrier and for diagnosing, preventing and/or treating leptomeningeal metastasis. In particular embodiments of the invention, the permeability of the blood CSF barrier is modulated by agonists or antagonists of Complement Component 3 (C3) or its receptor.
1 . A method of treating a subject suffering from a disorder of the central nervous system, comprising administering (i) an effective amount of an agonist of C3 or C3aR and (ii) an effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antiprotozoal agent, an antiparasitic agent, an anthelmintic agent and an anticancer agent.
2 . The method of claim 1 , wherein the subject is suffering from an infectious disease.
3 . The method of claim 2 , wherein the infectious disease is infective meningitis.
4 . The method of claim 1 , wherein the subject is suffering from a cancer.
5 . The method of claim 1 , wherein the subject is suffering from a degenerative disorder.
6 . The method of claim 1 , wherein the agonist is an agonist of C3.
7 . The method of claim 1 , wherein the agonist is an agonist of C3aR.
8 . The method of claim 1 , wherein the agonist of C3aR is selected from the group consisting of compound C4494, Benzeneacetamide, a-cyclohexyl-N-[1-[1-oxo-3-(3-pyridinyl) propyl]-4-piperidinyl]-, a-cyclohexyl-N-[1-[1-oxo-3-(3-pyridinyl) propyl]-4-piperidinyl]-benzeneacetamide, CAS Number 944997-60-8, and
9 . The method of claim 1 , wherein the agonist of C3 or C3aR has formula
wherein R is selected from the group consisting of phenyl, substituted phenyl, aryl, heteroaryl, pyridine, or substituted pyridine, lower alkyl alkoxy, and
10 . The method of claim 1 , wherein the agonist of C3 or C3aR has formula
wherein R is selected from the group consisting of phenyl, substituted phenyl, aryl, heteroaryl, pyridine, substituted pyridine,
11 . The method of claim 1 , wherein the agonist of C3 or C3aR is selected from the group consisting of Phe-Ile-Pro-Leu-Ala-Arg, Phe-Trp-Pro-Leu-Ala-Arg, Trp-Trp-Thr-Leu-Ala-Arg, Phe-Tyr-Thr-Leu-Ala-Arg, Phe-Trp-Thr-Leu-Ala-Arg, Phe-Leu-Thr-Leu-Ala-Arg, Phe-Leu-Gly-Leu-Ala-Arg, and Phe-Leu-Thr-Leu-Arg, and Tyr-Pro-Leu-Pro-Arg.
12 . The method of claim 1 , wherein the second therapeutic agent is selected from the group consisting of an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antiprotozoal agent, an antiparasitic agent, and an anthelmintic agent.
13 . The method of claim 1 , wherein the second therapeutic agent is an anticancer agent.
14 . A method of treating a subject suffering from a disorder of the central nervous system, consisting of administering (i) an effective amount of an agonist of C3 or C3aR and (ii) an effective amount of a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of an antimicrobial agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antiprotozoal agent, an antiparasitic agent, an anthelmintic agent and an anticancer agent.
15 . The method of claim 14 , wherein the subject is suffering from an infectious disease.
16 . The method of claim 15 , wherein the infectious disease is infective meningitis.
17 . The method of claim 14 , wherein the subject is suffering from a cancer.
18 . The method of claim 14 , wherein the subject is suffering from a degenerative disorder.
19 . The method of claim 14 , wherein the agonist of C3 or C3aR is selected from the group consisting of compound C4494, Benzeneacetamide, a-cyclohexyl-N-[1-[1-oxo-3-(3-pyridinyl) propyl]-4-piperidinyl]-, a-cyclohexyl-N-[1-[1-oxo-3-(3-pyridinyl) propyl]-4-piperidinyl]-benzeneacetamide, CAS Number 944997-60-8,
20 . The method of claim 14 , wherein the agonist of C3 or C3aR:
a) has formula
wherein R is selected from the group consisting of phenyl, substituted phenyl, aryl, heteroaryl, pyridine, or substituted pyridine, lower alkyl alkoxy, and
or
b) has formula
wherein R is selected from the group consisting of phenyl, substituted phenyl, aryl, heteroaryl, pyridine, substituted pyridine,
or
c) is Phe-Ile-Pro-Leu-Ala-Arg, Phe-Trp-Pro-Leu-Ala-Arg, Trp-Trp-Thr-Leu-Ala-Arg, Phe-Tyr-Thr-Leu-Ala-Arg, Phe-Trp-Thr-Leu-Ala-Arg, Phe-Leu-Thr-Leu-Ala-Arg, Phe-Leu-Gly-Leu-Ala-Arg, and Phe-Leu-Thr-Leu-Arg, and Tyr-Pro-Leu-Pro-Arg.