Targeted augmentation of nuclear gene output

A method of treating a subject to increase expression of a target protein or a target functional RNA by cells of the subject, the method comprising contacting the cells of the subject with an antisense oligomer, wherein the cells have a retained-intron-containing pre-mRNA (RIC pre-mRNA), wherein the RIC pre-mRNA comprises a retained intron, an exon flanking a 5′ splice site of the retained intron, and an exon flanking a 3′ splice site of the retained intron, and wherein the RIC pre-mRNA encodes the target protein or the target functional RNA;

• wherein the antisense oligomer binds to a targeted region of the RIC pre-mRNA;
• wherein the targeted region of the RIC pre-mRNA is in the retained intron within a region +6 relative to the 5′ splice site of the retained intron to −16 relative to the 3′ splice site of the retained intron;
• whereby the retained intron is constitutively spliced from the RIC pre-mRNA encoding the target protein or the target functional RNA, thereby increasing a level of mRNA encoding the target protein or the target functional RNA and increasing expression of the target protein or the target functional RNA by the cells of the subject;
• wherein the cells of the subject produce the target protein or the target functional RNA in a form that is fully-functional compared to a corresponding wild-type protein or wild-type RNA;
• wherein the subject has a condition caused by a deficient amount or activity of the target protein or a deficient amount or activity of the target functional RNA;
• wherein the condition is a disease or disorder;
• and wherein the disease or disorder is selected from the group consisting of thrombotic thrombocytopenic purpura, tuberous sclerosis complex, polycystic kidney disease, familial dysautonomia, retinitis pigmentosa type 10, retinitis pigmentosa type 11, cystic fibrosis, retinoblastoma, beta thalassemia, and sickle cell disease.

A method of treating a subject to increase expression of a target protein or a target functional RNA by cells of the subject, the method comprising contacting the cells of the subject with an antisense oligomer, wherein the cells have a retained-intron-containing pre-mRNA (RIC pre-mRNA), wherein the RIC pre-mRNA comprises a retained intron, an exon flanking a 5′ splice site of the retained intron, and an exon flanking a 3′ splice site of the retained intron, and wherein the RIC pre-mRNA encodes the target protein or the target functional RNA;

• wherein the antisense oligomer binds to a targeted region of the RIC pre-mRNA;
• wherein the targeted region of the RIC pre-mRNA is in the retained intron within a region +6 relative to the 5′ splice site of the retained intron to −16 relative to the 3′ splice site of the retained intron;
• whereby the retained intron is constitutively spliced from the RIC pre-mRNA encoding the target protein or the target functional RNA, thereby increasing a level of mRNA encoding the target protein or the target functional RNA and increasing expression of the target protein or the target functional RNA by the cells of the subject;
• wherein the cells of the subject produce the target protein or the target functional RNA in a form that is fully-functional compared to a corresponding wild-type protein or wild-type RNA;
• wherein the subject has a condition caused by a deficient amount or activity of the target protein or a deficient amount or activity of the target functional RNA;
• wherein the condition is a disease or disorder;
• and wherein the target protein or the target functional RNA and the RIC pre-mRNA are encoded by a gene selected from the group consisting of ADAMTS13, TSC1, PKD1, IKBKAP, IMPDH1, PRPF31, CFTR, RB1, HBG1, HBG2, and HBB.

A method of treating a subject to increase expression of a target protein or a target functional RNA by cells of the subject, the method comprising contacting the cells of the subject with an antisense oligomer, wherein the cells have a retained-intron-containing pre-mRNA (RIC pre-mRNA), wherein the RIC pre-mRNA comprises a retained intron, an exon flanking a 5′ splice site of the retained intron, and an exon flanking a 3′ splice site of the retained intron, and wherein the RIC pre-mRNA encodes the target protein or the target functional RNA;

• wherein the antisense oligomer binds to a targeted region of the RIC pre-mRNA comprising a sequence selected from the group consisting of SEQ ID NOS:
• 1-102 and 375-384;
• wherein the targeted region of the RIC pre-mRNA is in the retained intron within a region +6 relative to the 5′ splice site of the retained intron to −16 relative to the 3′ splice site of the retained intron;
• and
• whereby the retained intron is constitutively spliced from the RIC pre-mRNA encoding the target protein or the target functional RNA, thereby increasing a level of mRNA encoding the target protein or the target functional RNA and increasing expression of the target protein or the target functional RNA by the cells of the subject;
• wherein the cells of the subject produce the target protein or the target functional RNA in a form that is fully-functional compared to a corresponding wild-type protein or wild-type RNA.

A method of treating a subject to increase expression of a target protein or a target functional RNA by cells of the subject, the method comprising contacting the cells of the subject with an antisense oligomer, wherein the cells have a retained-intron-containing pre-mRNA (RIC pre-mRNA), wherein the RIC pre-mRNA comprises a retained intron, an exon flanking a 5′ splice site of the retained intron, and an exon flanking a 3′ splice site of the retained intron, and wherein the RIC pre-mRNA encodes the target protein or the target functional RNA;

• wherein the antisense oligomer binds to a targeted region of the RIC pre-mRNA;
• wherein the targeted region of the RIC pre-mRNA is in the retained intron within a region +6 relative to the 5′ splice site of the retained intron to −16 relative to the 3′ splice site of the retained intron;
• wherein the antisense oligomer comprises a sequence selected from the group consisting of SEQ ID NOs:
• 103-374 and 385-390;
• and
• whereby the retained intron is constitutively spliced from the RIC pre-mRNA encoding the target protein or the target functional RNA, thereby increasing a level of mRNA encoding the target protein or the target functional RNA and increasing expression of the target protein or the target functional RNA by the cells of the subject;
• wherein the cells of the subject produce the target protein or the target functional RNA in a form that is fully-functional compared to a corresponding wild-type protein or wild-type RNA.