Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA

Tanner, Gaby; Glaus, Esther; Barthelmes, Daniel; Ader, Marius; Fleischhauer, Johannes; Pagani, Franco; Berger, Wolfgang; Neidhardt, John

doi:10.1002/humu.20943

Cited by 1 publication

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“…The modified U1 snRNA approach has also been used for some other diseases caused by donor splice site mutations either to correct splicing defects or to detail mechanisms of aberrant splicing [16–21]. It is worth noting that mutations at the invariant GU site are generally not rescued, consistent with the critical importance of this dinucleotide in splicing.…”

Section: Rescue Of Coagulation Factor Expression By Splicing Modulationmentioning

confidence: 99%

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RNA‐based therapeutic approaches for coagulation factor deficiencies

Pinotti

Bernardi

Mas

et al. 2011

Journal of Thrombosis and Haemostasis

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To cite this article: Pinotti M, Bernardi F, Dal Mas A, Pagani F. RNA-based therapeutic approaches for coagulation factor deficiencies. J Thromb Haemost 2011; 9: 2143-52.Summary. Substitutive therapy has significantly ameliorated the quality of life of patients with coagulation factor deficiencies. However, there are some limitations that support research towards 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 the 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 exonintron junction, triggering synthesis of correct mRNA and secretion of functional factor (F)VII. (ii) Spliceosome-mediated RNA trans-splicing (SMaRT) between mutated and engineered pre-mRNAs produces normal FVIII mRNA and secretion of functional protein. (iii) Aminoglycoside drugs induce ribosome readthrough and suppress premature translation termination caused by nonsense mutations in FVII, 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.

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Section: Rescue Of Coagulation Factor Expression By Splicing Modulationmentioning

confidence: 99%

“…On the other hand, U1 snRNA is becoming an attractive molecule for its specific capacity to correct splicing mutations at the donor splice site [14–21].…”

Section: Introductionmentioning

confidence: 99%