Development and classification of therapeutic method for vascularEhlers-Danlos syndrome by mutation types

血管性埃勒斯-当洛斯综合征治疗方法的开发和按突变类型分类

• 批准号: 22591554
• 负责人: WATANABE Atsushi
• 金额: $ 2.83万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22591554/
• 关键词: 心臓大血管外科学; 家族性大動脈瘤; 血管型エーラス・ダンロス 症候群; 変異型; RNAi; COL3A1; 血管型エーラス・ダンロス症候群; コラーゲン

Vascular Ehlers-Danlos syndrome (vEDS), is a life-threatening dominantly inherited disorder caused by COL3A1 mutation. Although gene therapy is an important option for treatment of genetic disorders, addition of the defective gene is not applicable for dominant diseases such as vEDS. To establish a therapeutic strategy for vEDS, we examined the feasibility of two approaches in each mutation. First, we tested RNAi mediated inhibition of the mutant allele. We synthesized several small interfering RNA (siRNA) molecules targeting sequence specific for mutant mRNA and introduced into patient’s fibroblasts. Quantitative measurement of COL3A1 mRNA showed that mutant mRNA levels could be selectively decreased up to 80 % in splicing mutation and it was possible to increase the relative concentration of normal triple helix. Second, we attempted to increase theconcentration of normal COL3A1 mRNA, since half-dose of COL3A1 may not be sufficient to prevent vEDS symptoms. Lysyl oxidase(LOX)is a bifunctional protein carrying activities of both an extracellular enzyme that controls the maturation of collagen and elastin and an intracellular tranascriptional activator for the human collagen III promoter. When patient’s cells were transfected with mutant specific siRNA and LOX expression vector, specific inhibition of the mutant allele and enhancement of the normal allele wereobserved.

血管ehlers-danlos综合征（VEDS）是一种威胁生命的遗传性疾病，由Col3A1突变引起，用于治疗遗传疾病，并不适用于主要的DISEACH。对于VED，我们检查了每种突变中两种方法的可行性。 mRNA水平courd是最高80％的突变，并且可能是正常三重螺旋的相对浓度。 。

项目成果

家族性大動脈瘤の遺伝子変異スクリーニング方法に関する特許1件

1项与家族性主动脉瘤基因突变筛查方法相关的专利

• 发表时间: 2011

The first case of Tenascin-X deficient type Ehlers-Danlos syndrome in Japan.

日本首例 Tenascin-X 缺陷型 Ehlers-Danlos 综合征病例。

• 发表时间: 2012
• 作者: Watanabe A;Hatakeyama M;Tsunoda R;Matsumoto K;Kawame H;Shimada T.
• 通讯作者: Shimada T.

A NOVEL MUTATION SCREENING SYSTEM FOR VASCULAR TYPEEHLERS-DANLOS SYNDROME (VEDS, EDS TYPE IV) USING HIGH RESOLUTION MELTING CURVE ANALYSIS (HRMCA)

使用高分辨率熔解曲线分析 (HRMCA) 的新型血管型 EHLERS-DANLOS 综合征（VEDS、EDS IV 型）突变筛选系统

• 发表时间: 2010
• 作者: Banyar Than Naing;渡邉淳 ,佐々木元子,圷 宏一,小齊平聖治,弦間 昭彦,島田隆;Atsushi Watanabe
• 通讯作者: Atsushi Watanabe

難治性疾患克服事業によ る血管型エーラスダンロス症候群の実態調査

通过疑难杂症攻克工程调查血管性埃勒斯-当洛斯综合征的现状

• 发表时间: 2010
• 期刊: 日本遺伝カウンセリング学会誌
• 作者: 古庄知己;渡邉淳 ,森崎裕子,福嶋義光,籏持淳
• 通讯作者: 渡邉淳 ,森崎裕子,福嶋義光,籏持淳

n intronic mutation affecting pre-mRNA splicing in the COL3A1 gene as novel mechanisms causing vascular Ehlres-Danlos syndrome.

n 内含子突变影响 COL3A1 基因中的前 mRNA 剪接，作为引起血管 Ehlres-Danlos 综合征的新机制。

• 发表时间: 2012
• 作者: Watanabe A;Hatakeyama M;Tsunoda R;Matsumoto K;Kawame H;Shimada T.;A. Watanabe
• 通讯作者: A. Watanabe