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. 2023 Oct 17:34:102042.
doi: 10.1016/j.omtn.2023.102042. eCollection 2023 Dec 12.

RNA therapy is shining for genetic diseases

Zhi-Ming Zheng  1
Affiliations

RNA therapy is shining for genetic diseases

Zhi-Ming Zheng. Mol Ther Nucleic Acids. .
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Correction or suppression of aberrant RNA splicing by specific RNA-targeted approaches and SF3B1-targeted splicing modulators (A) AONs or small interfering RNAs (siRNAs) in RNA therapy of genetic diseases. A G-to-U mutation in FKTN intron 5 activates a 64-nt pseudo-exon (P) inclusion in FKTN mRNA and reduction of glycosylated α-DG in FCMD patients. A BP-AON specifically targeting to the BPS upstream of the pseudo-exon promotes the pseudo-exon exclusion for production of the normal FKTN mRNA. SMN2 gene encoding 9 exons has a C- to-T mutation in exon 7 in SMA patients, which promotes exon 7 skipping in SMN2 pre-mRNA splicing, resulting in a truncated dysfunctional SMN2 protein to cause severe SMA. The AON-based Nusingersen (Spinraza) targeting an intronic splicing silencer in SMN2 intron 7 prevents the exon 7 skipping and modifies clinical outcome of SMA., Transthyretin (TTR) transports the thyroid hormone thyroxine and retinol to the liver and its misfolding and aggregation is associated with hereditary TTR amyloidosis. The siRNA-based Patisiran (Onpattro) targeting the 3′ UTR (white box) of both wild-type and mutant TTR mRNAs induces RNA degradation to reduce the production of TTR protein. Figures are not in scale. (B) SF3B1 facilitates U2 binding to a branchpoint A in BPS to initiate RNA splicing. Small-molecule splicing modulators targeting SF3B1 in regulation of RNA splicing are currently under investigations for possible anticancer therapies and treatment of genetic disorders.
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