Glucocorticoid modulation of nucleic acid-mediated immune stimulation
The present invention provides methods for minimizing or inhibiting immune responses to immunostimulatory nucleic acids by pretreating with one or more doses of a glucocorticoid prior to nucleic acid administration. The nucleic acids are typically administered using a lipid-based carrier system such as a nucleic acid-lipid particle or liposome. As a result, patients following a glucocorticoid dosing regimen advantageously benefit from nucleic acid therapy without suffering any of the immunostimulatory side-effects associated with such therapy.
1 . A method for modulating an immune response associated with administration of an immunostimulatory nucleic acid, the method comprising administering to a mammal a dose of a glucocorticoid.
2 . The method in accordance with claim 1 , wherein the glucocorticoid is administered prior to administering the nucleic acid.
3 . The method in accordance with claim 1 , wherein the glucocorticoid is administered during nucleic acid administration.
4 . The method in accordance with claim 1 , wherein the glucocorticoid is administered after administering the nucleic acid.
5 . The method in accordance with claim 1 , wherein the glucocorticoid is administered by a route selected from the group consisting of oral, intranasal, intravenous, intraperitoneal, intramuscular, intra-articular, intralesional, intratracheal, subcutaneous, and intradermal.
6 . (canceled)
7 . The method in accordance with claim 1 , wherein the glucocorticoid inhibits the immune response.
8 . The method in accordance with claim 7 , wherein the immune response comprises production of a cytokine.
9 . (canceled)
10 . The method in accordance with claim 1 , wherein the glucocorticoid is selected from the group consisting of hydrocortisone, cortisone, corticosterone, deoxycorticosterone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, mometasone, triamcinolone, beclomethasone, fludrocortisone, aldosterone, fluticasone, clobetasone, clobetasol, loteprednol, pharmaceutically acceptable salts thereof, and mixtures thereof.
11 . The method in accordance with claim 1 , wherein the glucocorticoid is dexamethasone.
12 - 16 . (canceled)
17 . The method in accordance with claim 1 , wherein the nucleic acid is selected from the group consisting of DNA, RNA, a small interfering RNA (siRNA), a plasmid, an antisense oligonucleotide, a ribozyme, and mixtures thereof.
18 . The method in accordance with claim 1 , wherein the nucleic acid is administered using a lipid-based carrier system.
19 - 20 . (canceled)
21 . The method in accordance with claim 18 , wherein the lipid-based carrier system is selected from the group consisting of a nucleic acid-lipid particle, liposome, micelle, virosome, nucleic acid complex, and mixtures thereof.
22 . The method in accordance with claim 18 , wherein the lipid-based carrier system is a nucleic acid-lipid particle.
23 . The method in accordance with claim 22 , wherein the nucleic acid-lipid particle comprises:
(a) the nucleic acid;
(b) a cationic lipid; and
(c) a non-cationic lipid.
24 . (canceled)
25 . The method in accordance with claim 23 , wherein the cationic lipid is DLinDMA.
26 - 27 . (canceled)
28 . The method in accordance with claim 23 , further comprising a conjugated lipid that inhibits aggregation of particles.
29 . The method in accordance with claim 28 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid selected from the group consisting of a PEG-diacylglycerol, a PEG dialkyloxypropyl, a PEG-phospholipid, a PEG-ceramide, and a mixture thereof.
30 - 37 . (canceled)
38 . The method in accordance with claim 23 , further comprising cholesterol.
39 - 40 . (canceled)
41 . The method in accordance with claim 23 , wherein the nucleic acid is fully encapsulated in the particle.
42 - 44 . (canceled)
45 . The method in accordance with claim 2 , further comprising administering to the mammal a second dose of a glucocorticoid prior to administering the nucleic acid.
46 - 51 . (canceled)
52 . The method in accordance with claim 45 , further comprising administering to the mammal a third dose of a glucocorticoid after administering the nucleic acid.
53 - 58 . (canceled)
59 . The method in accordance with claim 1 , wherein the mammal is a human.