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Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema

机译:C1酯酶抑制剂遗传性血管模型中C1酯酶抑制剂缺乏的基因治疗

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Background Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. Methods To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63 +/-) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Results Systemic administration of AAVrh.10hC1EI to the S63 +/- mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. Conclusion A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.
机译:背景技术遗传性血统(Hae)是一种危及生命的常染色体显性疾病,其特征是面部,上气道,oropharynx,四肢,生殖器和胃肠道的不可预测的,情节肿胀。几乎所有HAE病例都是由六种基因的突变引起的,导致功能性等离子体C1酯酶抑制剂(C1EI)的缺乏,丝氨酸蛋白酶抑制剂通常抑制接触,补体和纤维蛋白溶解系统中的蛋白酶。 HAE的目前治疗包括具有减毒的雌激素或人血浆衍生的C1EI的长期预防,以及用人血浆衍生或重组C1EI,Bradykinin和Kallikrein抑制剂的急性发作的管理,每个抑制剂需要重复给药。作为有效治疗Hae的方法,我们假设表达正常人C1酯酶抑制剂(AAVRH.10HC1EI)的遗传序列的一次性静脉施用腺相关病毒(AAV)基因转移载体的一次性静脉内施用提供足以防止血管模型发作的持续循环C1EI水平。研究AAVRH.10HC1EI,我们使用CRISPR / CAS9技术的疗效来创建杂合子C1EI缺陷的小鼠模型(S63 +/-),该模型(S63 +/-)分享与人类的HAE相关的特征,包括降低的等离子体C1EI和C4水平。表型,这些小鼠具有增加皮肤和内脏的血管渗透性。结果Aavrh.10HC1EI的全身施用至S63 +/-小鼠,导致持续的人C1EI活性水平高于预测的治疗水平和皮肤和内器官血管泄漏的校正。结论含有AAVRH.10HC1EI的单一治疗有可能在受影响个体的血管模型攻击中提供长期保护。

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