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A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease

Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn’s disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the...

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Autores principales: Di Fusco, Davide, Marafini, Irene, Stolfi, Carmine, Troncone, Edoardo, Onali, Sara, Lolli, Elisabetta, Caprioli, Flavio, Mazza, Stefano, Raffaella, Cascella, Manzo, Laura, Borgiani, Paola, Giuffrida, Paolo, Di Sabatino, Antonio, Monteleone, Ivan, Monteleone, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460430/
https://www.ncbi.nlm.nih.gov/pubmed/32707955
http://dx.doi.org/10.3390/biomedicines8080234
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author Di Fusco, Davide
Marafini, Irene
Stolfi, Carmine
Troncone, Edoardo
Onali, Sara
Lolli, Elisabetta
Caprioli, Flavio
Mazza, Stefano
Raffaella, Cascella
Manzo, Laura
Borgiani, Paola
Giuffrida, Paolo
Di Sabatino, Antonio
Monteleone, Ivan
Monteleone, Giovanni
author_facet Di Fusco, Davide
Marafini, Irene
Stolfi, Carmine
Troncone, Edoardo
Onali, Sara
Lolli, Elisabetta
Caprioli, Flavio
Mazza, Stefano
Raffaella, Cascella
Manzo, Laura
Borgiani, Paola
Giuffrida, Paolo
Di Sabatino, Antonio
Monteleone, Ivan
Monteleone, Giovanni
author_sort Di Fusco, Davide
collection PubMed
description Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn’s disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the drug, but factors contributing to the failure of this study remain unknown. Here, we analysed the frequency in CD of rs144204026 C/T single nucleotide polymorphism (SNP), which maps on the corresponding region targeted by the Smad7 AS contained in the Mongersen formulation and examined whether such a variant allele affects the ability of Smad7 AS to knockdown Smad7. Methods: rs144204026 SNP frequency was evaluated in two independent Italian cohorts of Crohn’s disease patients and normal controls. Genotyping was performed by allelic discrimination assay. Smad7 expression was evaluated in wild-type or heterozygous PBMCs treated with Smad7 AS. Results: No TT genotype was seen in CD patients and controls. Heterozygous genotype was more frequent in CD patients of both cohort 1 (11/235, 4.68%) and cohort 2 (8/122, 6.56%) as compared to controls (6/363, 1.65%; p = 0.029 and p = 0.01 respectively). Overall, a statistically significant association was observed between the T variant allele and CD patients’ susceptibility (p = 0.008; OR = 3.28, 95%CI: 1.3–8.3). Smad7 AS down-regulated Smad7 RNA independently of the presence of the variant allele. Conclusions: This is the first study to show an association between Smad7 rs144204026 SNP and CD patients. Data indicate that such a variant does not negatively influence the in vitro inhibitory effect of Smad7 AS on Smad7.
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spelling pubmed-74604302020-09-03 A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease Di Fusco, Davide Marafini, Irene Stolfi, Carmine Troncone, Edoardo Onali, Sara Lolli, Elisabetta Caprioli, Flavio Mazza, Stefano Raffaella, Cascella Manzo, Laura Borgiani, Paola Giuffrida, Paolo Di Sabatino, Antonio Monteleone, Ivan Monteleone, Giovanni Biomedicines Article Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effective in pre-clinical studies and initial clinical trials in Crohn’s disease (CD) patients. A recent phase 3 trial was discontinued due to an apparent inefficacy of the drug, but factors contributing to the failure of this study remain unknown. Here, we analysed the frequency in CD of rs144204026 C/T single nucleotide polymorphism (SNP), which maps on the corresponding region targeted by the Smad7 AS contained in the Mongersen formulation and examined whether such a variant allele affects the ability of Smad7 AS to knockdown Smad7. Methods: rs144204026 SNP frequency was evaluated in two independent Italian cohorts of Crohn’s disease patients and normal controls. Genotyping was performed by allelic discrimination assay. Smad7 expression was evaluated in wild-type or heterozygous PBMCs treated with Smad7 AS. Results: No TT genotype was seen in CD patients and controls. Heterozygous genotype was more frequent in CD patients of both cohort 1 (11/235, 4.68%) and cohort 2 (8/122, 6.56%) as compared to controls (6/363, 1.65%; p = 0.029 and p = 0.01 respectively). Overall, a statistically significant association was observed between the T variant allele and CD patients’ susceptibility (p = 0.008; OR = 3.28, 95%CI: 1.3–8.3). Smad7 AS down-regulated Smad7 RNA independently of the presence of the variant allele. Conclusions: This is the first study to show an association between Smad7 rs144204026 SNP and CD patients. Data indicate that such a variant does not negatively influence the in vitro inhibitory effect of Smad7 AS on Smad7. MDPI 2020-07-22 /pmc/articles/PMC7460430/ /pubmed/32707955 http://dx.doi.org/10.3390/biomedicines8080234 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Di Fusco, Davide
Marafini, Irene
Stolfi, Carmine
Troncone, Edoardo
Onali, Sara
Lolli, Elisabetta
Caprioli, Flavio
Mazza, Stefano
Raffaella, Cascella
Manzo, Laura
Borgiani, Paola
Giuffrida, Paolo
Di Sabatino, Antonio
Monteleone, Ivan
Monteleone, Giovanni
A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease
title A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease
title_full A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease
title_fullStr A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease
title_full_unstemmed A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease
title_short A Novel Smad7 Genetic Variant Mapping on the Genomic Region Targeted by Mongersen Is Associated with Crohn’s Disease
title_sort novel smad7 genetic variant mapping on the genomic region targeted by mongersen is associated with crohn’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460430/
https://www.ncbi.nlm.nih.gov/pubmed/32707955
http://dx.doi.org/10.3390/biomedicines8080234
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