VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy.
VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy.
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DOI：
10.1016/j.omtm.2021.03.013
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发表时间：
2021-06-11
期刊：
影响因子：
--
通讯作者：
Keefe D
中科院分区：
文献类型：
--
作者：
Bosco J;Zhou Z;Gabriëls S;Verma M;Liu N;Miller BK;Gu S;Lundberg DM;Huang Y;Brown E;Josiah S;Meiyappan M;Traylor MJ;Chen N;Asakura A;De Jonge N;Blanchetot C;de Haard H;Duffy HS;Keefe D
杜氏肌营养不良症的特征在于肌肉的结构变性，其由于一氧化氮合酶诱导的血管舒张的丧失而被局部功能性缺血所加剧。已经提出了旨在增加血管灌注的治疗策略。为此，我们开发了与血管内皮生长因子（VEGF）受体VEGFR-1（Flt-1）及其可溶性剪接变体同种型（sFlt-1）结合的单克隆抗体（mAb），导致游离VEGF和促血管生成信号传导水平升高。先导嵌合mAb 21 B3对人和小鼠sFlt-1具有高亲和力和特异性，并以竞争性方式抑制VEGF与sFlt-1的结合。在杜氏肌营养不良症mdx小鼠模型中进行的概念验证研究表明，静脉注射21 B3可导致VEGF水平升高，血管化和肌肉血流量增加，治疗6-12周后纤维化减少。治疗4周后还观察到更大的肌肉力量。对mAb的人源化形式27 H6进行了工程改造，并证明了相当的药理学作用。总体而言，在mdx小鼠中施用抗Flt-1 mAb抑制VEGF：Flt-1相互作用，促进血管生成，并改善肌肉功能。这些研究表明Flt-1抑制对Duchenne肌营养不良症患者具有潜在的治疗益处。开发了具有高亲和力和特异性的抑制血管内皮生长因子（VEGF）受体（Flt-1）的人-鼠交叉反应性单克隆抗体（mAb）。在杜氏肌营养不良症（DMD）的mdx小鼠模型中，mAb增加了VEGF水平、血管形成和肌肉功能，并减少了纤维化，这表明对DMD具有潜在的治疗益处。
Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mdx mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6–12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mdx mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy. Human-mouse cross-reactive monoclonal antibodies (mAbs) inhibiting the vascular endothelial growth factor (VEGF) receptor (Flt-1) with high affinity and specificity were developed. In the mdx mouse model of Duchenne muscular dystrophy (DMD), the mAbs increased VEGF levels, vascularization, and muscle function and decreased fibrosis, suggesting potential therapeutic benefit for DMD.
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