RNA‐based therapeutic approaches for coagulation factor deficiencies

摘要: Summary.  Substitutive therapy has significantly ameliorated the quality of life patients with coagulation factor deficiencies. However, there are some limitations that support research towards alternative therapeutic approaches. Here we focus on rescue biosynthesis by targeting RNA processing and translation, which would permit restoration altered gene expression while maintaining regulation in physiological tissues. The essential prerequisite three reported RNA-based correction approaches (i–iii), rely mutation types applicable even to large size mRNAs, is presence cells precursor (pre-mRNA) or mature mRNA forms. (i) In F7 gene, modification small nuclear U1 (U1 snRNA), key component spliceosomal ribonucleoprotein, re-directs correct usage a mutated exon–intron junction, triggering synthesis secretion functional (F)VII. (ii) Spliceosome-mediated trans-splicing (SMaRT) between engineered pre-mRNAs produces normal FVIII protein. (iii) Aminoglycoside drugs induce ribosome readthrough suppress premature translation termination caused nonsense mutations FVII, VIII IX. rescued levels ranged from very low (aminoglycosides) moderate snRNA SMaRT), could result amelioration disease phenotypes. These findings prompt further studies aimed at demonstrating clinical translatability strategies, might open new avenues treatment