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Rna-Based Therapeutic Approaches for Coagulation Factor Deficiencies.

By Pinotti M, Bernardi F, Dal Mas A and Pagani F


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

Topics: splicing, RNA based therapies
Year: 2011
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