TY - JOUR
T1 - A novel Smad7 genetic variant mapping on the genomic region targeted by mongersen is associated with Crohn's disease
AU - Di Fusco, Davide
AU - Marafini, Irene
AU - Stolfi, Carmine
AU - Troncone, Edoardo
AU - Onali, Sara
AU - Lolli, Elisabetta
AU - Caprioli, Flavio
AU - Mazza, Stefano
AU - Raffaella, Cascella
AU - Manzo, Laura
AU - Borgiani, Paola
AU - Giuffrida, Paolo
AU - Di Sabatino, Antonio
AU - Monteleone, Ivan
AU - Monteleone, Giovanni
PY - 2020/8
Y1 - 2020/8
N2 - Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effiective 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 effiect of Smad7 AS on Smad7.
AB - Background: Down-regulation of Smad7 with a specific Smad7 antisense (AS) oligonucleotide-containing oral drug (Mongersen) was effiective 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 effiect of Smad7 AS on Smad7.
KW - Crohn's disease
KW - Inflammatory bowel disease
KW - Single nucleotide polymorphisms
KW - Smad7
KW - Ulcerative colitis
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U2 - 10.3390/BIOMEDICINES8080234
DO - 10.3390/BIOMEDICINES8080234
M3 - Article
AN - SCOPUS:85089678395
VL - 8
JO - Biomedicines
JF - Biomedicines
SN - 2227-9059
IS - 8
M1 - 234
ER -