Approcci terapeutici RNA-based

La maggior parte dei geni va incontro a splicing alternativo e molte mutazioni (>30%) vanno ad alterare questo processo di maturazione dell'RNA. Attualmente sono disponibili diverse strategie in grado di modulare il processamento dell'RNA messaggero. Nel nostro laboratorio vengono esplorati questi approcci di modulazione al fine di ripristinare il corretto processamento dell'RNA per scopi terapeutici.

 

Pubblicazioni:


OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfash mice, and govern susceptibility to RNA-based therapies. Sacchetto C, Peretto L, Baralle F, Maestri I, Tassi F, Bernardi F, van de Graaf SFJ, Pagani F, Pinotti M, Balestra D.

Mol Med. 2021 Dec 14;27(1):157.

doi: 10.1186/s10020-021-00418-9.


Dissection of pleiotropic effects of variants in and adjacent to F8 exon 19 and rescue of mRNA splicing and protein function. Lombardi S, Leo G, Merlin S, Follenzi A, McVey JH, Maestri I, Bernardi F, Pinotti M, Balestra D.

Am J Hum Genet. 2021 Aug 5;108(8):1512-1525.

doi: 10.1016/j.ajhg.2021.06.012.

 

An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency. Balestra D, Ferrarese M, Lombardi S, Ziliotto N, Branchini A, Petersen N, Bosma P, Pinotti M, van de Graaf SFJ.

Int J Mol Sci. 2020 Nov 19;21(22):8735.

doi: 10.3390/ijms21228735.

 

A Compensatory U1snRNA Partially Rescues FAH Splicing and Protein Expression in a Splicing-Defective Mouse Model of Tyrosinemia Type I. Balestra D, Scalet D, Ferrarese M, Lombardi S, Ziliotto N, C Croes C, Petersen N, Bosma P, Riccardi F, Pagani F, Pinotti M, van de Graaf SFJ.

Int J Mol Sci. 2020 Mar 20;21(6)

doi: 10.3390/ijms21062136

 

Next-generation sequencing and recombinant expression characterized aberrant splicing mechanisms and provided correction strategies in factor VII deficiency. Ferraresi P, Balestra D, Guittard C, Buthiau D, Pan-Petesh B, Maestri I, Farah R, Pinotti M, Giansily-Blaizot M.

Haematologica. 2020 Mar;105(3):829-837

doi: 10.3324/haematol.2019.217539

 

An Altered Splicing Registry Explains the Differential ExSpeU1-Mediated Rescue of Splicing Mutations Causing Haemophilia A. Balestra D1, Maestri I, Branchini A, Ferrarese M, Bernardi F, Pinotti M.

Front Genet. 2019 Oct 10;10:974.

doi: 10.3389/fgene.2019.00974

 

Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy. Balestra D, Giorgio D, Bizzotto M, Fazzari M, Ben Zeev B, Pinotti M, Landsberger N, Frasca A.

Int J Mol Sci. 2019 Aug 24;20(17)

doi: 10.3390/ijms20174130

 

Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies.Balestra D, Branchini A.

Int J Mol Sci. 2019 Jun 21;20(12).

doi: 10.3390/ijms20123036

 

Disease-causing variants of the conserved +2T of 5' splice sites can be rescued by engineered U1snRNAs. Scalet D, Maestri I, Branchini A, Bernardi F, Pinotti M, Balestra D.

Hum Mutat. 2019 Jan;40(1):48-52.

doi: 10.1002/humu.23680


The somatic FAH C.1061C>A change counteracts the frequent FAH c.1062+5G>A mutation and permits U1snRNA-based splicing correction. Scalet D, Sacchetto C, Bernardi F, Pinotti M, van de Graaf SFJ, Balestra D.
J Hum Genet. 2018 May;63(5):683-686.

doi: 10.1038/s10038-018-0427-x

 

Exploring Splicing-Switching Molecules For Seckel Syndrome Therapy. Scalet D, Balestra D, Rohban S, Bovolenta M, Perrone D, Bernardi F, Campaner S, Pinotti M.

Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):15-20.

doi: 10.1016/j.bbadis.2016.09.011.

 

An Exon-Specific U1snRNA Induces a Robust Factor IX Activity in Mice Expressing Multiple Human FIX Splicing Mutants. Balestra D, Scalet D, Pagani F, Rogalska ME, Mari R, Bernardi F, Pinotti M.

Mol Ther Nucleic Acids. 2016 Oct 4;5(10):e370.

doi: 10.1038/mtna.2016.77

 

Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function. Tajnik M, Rogalska ME, Bussani E, Barbon E, Balestra D, Pinotti M, Pagani F.
PLoS Genet. 2016 May 26;12(5):e1006082.

doi: 10.1371/journal.pgen.1006082

 

Regulation of a strong F9 cryptic 5'ss by intrinsic elements and by combination of tailored U1snRNAs with antisense oligonucleotides. Balestra D, Barbon E, Scalet D, Cavallari N, Perrone D, Zanibellato S, Bernardi F, Pinotti M.

Hum Mol Genet. 2015 Sep 1;24(17):4809-16

doi: 10.1093/hmg/ddv205

An engineered U1 small nuclear RNA rescues splicing defective coagulation F7 gene expression in mice. Balestra D, Faella A, Margaritis P, Cavallari N, Pagani F, Bernardi F, Arruda VR, Pinotti M.

J Thromb Haemost. 2014 Feb;12(2):177-85.

doi: 10.1111/jth.12471

Activation of a cryptic splice site in a potentially lethal coagulation defect accounts for a functional protein variant. Cavallari N, Balestra D, Branchini A, Maestri I, Chuamsunrit A, Sasanakul W, Mariani G, Pagani F, Bernardi F, Pinotti M.

Biochim Biophys Acta. 2012 Jul;1822(7):1109-13.

doi: 10.1016/j.bbadis.2012.03.001

 

An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Fernandez Alanis E, Pinotti M, Dal Mas A, Balestra D, Cavallari N, Rogalska ME, Bernardi F, Pagani F.

Hum Mol Genet. 2012 Jun 1;21(11):2389-98.

doi: 10.1093/hmg/dds045

 

Rescue of coagulation factor VII function by the U1+5A snRNA. Pinotti M1, Balestra D, Rizzotto L, Maestri I, Pagani F, Bernardi F.

Blood. 2009 Jun 18;113(25):6461-4.

doi: 10.1182/blood-2009-03-207613


U1-snRNA-mediated rescue of mRNA processing in severe factor VII deficiency. Pinotti M, Rizzotto L, Balestra D, Lewandowska MA, Cavallari N, Marchetti G, Bernardi F, Pagani F.

Blood. 2008 Mar 1;111(5):2681-4.

doi: 10.1182/blood-2007-10-117440