Lipid encapsulated interfering RNA

Abstract

The present invention provides compositions and methods for silencing gene expression by delivering nucleic acid-lipid particles comprising a siRNA molecule to a cell.

Description

FIELD OF THE INVENTION The present invention relates to compositions and methods for the therapeutic delivery of a nucleic acid by delivering a serum-stable lipid delivery vehicle encapsulating the nucleic acid to provide efficient RNA interference (RNAi) in a cell or mammal. More particularly, the present invention is directed to using a small interfering RNA (siRNA) encapsulated in a serum-stable lipid particle having a small diameter suitable for systemic delivery. BACKGROUND OF THE INVENTION RNA interference (RNAi) is an evolutionarily conserved, sequence specific mechanism triggered by double stranded RNA (dsRNA) that induces degradation of complementary target single stranded mRNA and “silencing” of the corresponding translated sequences (McManus and Sharp, Nature Rev. Genet. 3:737 (2002)). RNAi functions by enzymatic cleavage of longer dsRNA strands into biologically active “short-interfering RNA” (siRNA) sequences of about 21-23 nucleotides in length (Elbashir, et al., Gen...

AI Technical Summary

Benefits of technology

Another embodiment of the present invention provides methods for in vivo delivery of siRNA. A nucleic acid-lipid particle comprising a cationic lipid, a non-cationic lipid, a conjugated lipid that inhibits aggregation of particles, and siRNA is administered (e.g., intravenously, subcutaneously, intraperitoneally, or subdermally) to a subject (e.g., a mammal such as a human). In some embodiments, the invention provides methods for in vivo delivery of interfering RNA to the liver of a mammalian subject.

A further embodiment of the present invention provides a method of treating a disease or disorder in a mammalian subject. A therapeutically effective amount of a nucleic acid-lipid particle comprising a cationic lipid, a non-cationic lipid, a conjugated lipid that inhibits aggregation of particles, and siRNA is administered to the mammalian subject (e.g., a rodent such as a mouse, a primate such as a human or a monkey) with the disease or disorder. In some embodiments, the disease or disorder is associated with expression and / or overexpression of a gene and expression or overexpression of the gene is silenced by the siRNA. In some embodiments, the disease is a viral disease such as, for example, hepatitis (e.g., Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Hepatitis G, or a combination thereof). In some embodiment, the disease or disorder is a liver disease or disorder, such as, for example, dyslipidemia.

Problems solved by technology

Viral vectors are relatively efficient gene delivery systems, but suffer from a variety of safety concerns, such as potential for undesired immune responses.

In addition, these systems induce immune responses that compromise delivery with subsequent injections.

Cationic liposome complexes, however, are large, poorly defined systems that are not suited for systemic applications and can elicit considerable toxic side effects (Harrison, et al., Biotechniques 19:816 (1995); Li, et al., The Gene 4:891 (1997); Tam, et al, Gene Ther.

Images