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
Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", 00133 Rome, Italy.
Biomedicines. 2020 Jul 22;8(8):234. doi: 10.3390/biomedicines8080234.
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.
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. expression was evaluated in or heterozygous PBMCs treated with Smad7 AS.
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%; = 0.029 and = 0.01 respectively). Overall, a statistically significant association was observed between the T variant allele and CD patients' susceptibility ( = 0.008; OR = 3.28, 95%CI: 1.3-8.3). Smad7 AS down-regulated RNA independently of the presence of the variant allele.
This is the first study to show an association between 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.
含特定Smad7反义（AS）寡核苷酸的口服药物（Mongersen）使Smad7表达下调，在克罗恩病（CD）患者的临床前研究和初始临床试验中有效。最近一项3期试验因该药物明显无效而终止，但导致该研究失败的因素仍不清楚。在此，我们分析了rs144204026 C/T单核苷酸多态性（SNP）在CD中的频率，该SNP位于Mongersen制剂中所含Smad7 AS靶向的相应区域，并研究这种变异等位基因是否影响Smad7 AS敲低Smad7的能力。
在两个独立的意大利克罗恩病患者队列和正常对照中评估rs144204026 SNP频率。通过等位基因鉴别分析进行基因分型。在用Smad7 AS处理的纯合或杂合外周血单核细胞（PBMC）中评估Smad7表达。
在CD患者和对照中均未观察到TT基因型。与对照（6/363，1.65%；P = 0.029和P = 0.01）相比，队列1（11/235，4.68%）和队列2（8/122，6.56%）的CD患者中杂合基因型更为常见。总体而言，观察到T变异等位基因与CD患者易感性之间存在统计学显著关联（P = 0.008；OR = 3.28，95%CI：1.3 - 8.3）。无论变异等位基因是否存在，Smad7 AS均能下调Smad7 RNA。
这是第一项显示rs144204026 SNP与CD患者之间存在关联的研究。数据表明这种变异不会对Smad7 AS对Smad7的体外抑制作用产生负面影响。
