Targeted augmentation of nuclear gene output

A method of treating a human subject having an autosomal recessive disorder characterized by deficient expression or function of a functional target protein due to a hypomorphic mutation in a gene encoding the functional target protein, wherein a retained-intron-containing pre-mRNA (RIC pre-mRNA) transcribed from the gene in cells of the human subject comprises a rate-limiting retained intron, wherein the method increases expression of the functional target protein by the cells of the human subject that have the RIC pre-mRNA, the method comprising:

• contacting the cells of the human subject with an antisense oligomer (ASO), wherein the RIC pre-mRNA comprises said rate-limiting retained intron, an exon flanking a 5′ splice site of said retained intron, and an exon flanking a 3′ splice site of said rate-limiting retained intron;
• and
• modulating splicing of said rate-limiting retained intron from the RIC pre-mRNA encoding the functional target protein, whereby accumulation of the RIC pre-mRNA in nuclei of the cells or degradation of the RIC pre-mRNA in the cells is reduced compared to equivalent cells not contacted with the antisense oligomer, thereby increasing a level of mRNA encoding the functional target protein and increasing expression of the functional target protein by the cells of the human subject having the autosomal recessive disorder, and wherein the antisense oligomer binds to a targeted region within:
• (a) a region +6 relative to the 5′ splice site of said retained intron to −16 relative to the 3′ splice site of the retained intron;
• (b) a region +2e to −4e in the exon flanking the 5′ splice site of said retained intron;
• or
• (c) a region +2e to −4e in the exon flanking the 3′ splice site of said retained intron.