Methods and compositions for treatment of cholesteryl ester storage disease

A method of modulating expression of a lysosomal acid lipase (LAL) protein encoded by an LIPA gene, by cells having a skippable-exon-containing pre-mRNA (SEC pre-mRNA), the SEC pre-mRNA comprising the skippable exon, an intron flanking the 5′ splice site of the skippable exon, and an intron flanking the 3′ splice site of the skippable exon, wherein the SEC pre-mRNA is transcribed from the LIPA gene in the cells and encodes the LAL protein, the method comprising contacting the cells with an antisense oligomer (ASO) complementary to a targeted portion of the SEC pre-mRNA encoding the LAL protein, whereby the skippable exon is retained in an mRNA processed from the SEC pre-mRNA encoding the LAL protein, thereby modulating the level of mRNA encoding LAL protein and modulating the expression of LAL protein in the cells, wherein the skippable exon is exon 8, and wherein the targeted portion of the SEC pre-mRNA is within

• (a) position +6 to position +28 in intron 8;
• or
• (b) position +61 to position +98 in intron 8.