METHOD FOR ADMINISTRATION OF THERAPEUTIC AGENTS, INCLUDING ANTISENSE, WITH REPEAT DOSING

摘要

Treatment or prevention of a disease characterized by aberrant expression of a gene in a mammalian subject is achieved using lipid-encapsulated therapeutic nucleic acid particles made from a therapeutic nucleic acid component that hybridizes specifically with the aberrantly expressed gene to reduce its expression in the subject encapsulated within a lipid particle. The lipid particle is formed from a lipid mixture including a stericbarrier lipid component selected from among lipids that prevent particle aggregation during lipid-nucleic acid particle formation and which exchange out of the lipid particle at a rate greater than PEG-CerC20, and is administered in a therapeutically effective or prophylactic amount to the mammalian subject in a plurality of separate doses separated in time by intervals of up to eight weeks. The particles are preferably formulated using a PEG-modified or polyamide oligomer-modified lipid as the first lipid component. To achieve high loading levels, an effective method for preparation of the lipid-encapsulated nucleic acid particles involves the use of a lipid mixture comprising at least the first lipid component and a protonatable lipid component selected from among lipids containing a protonatable group that has a pKa such that the lipid is in a cationic form at a pH below the pKa and a neutral form at around physiological pH. The method the invention is particularly useful for therapy using lipid-encapsulated antisense nucleic acids or ribozymes. In a more general sense, however, the method of the invention may also be used for delivery of non-cytotoxic lipid-encapsulated therapeutic agents generally in a repeat dosing regimen.