Butler Susan S, Date Kenjiro, Okumura Takashi, Lueck Cooper, Ghosh Bidyut, Maitra Anirban, Suh Junghae
Department of Bioengineering, Rice University, Houston, TX, USA.
Departments of Translational Molecular Pathology and Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gene Ther. 2022 Apr;29(3-4):138-146. doi: 10.1038/s41434-021-00255-9. Epub 2021 May 6.
Adeno-associated virus' (AAV) relatively simple structure makes it accommodating for engineering into controllable delivery platforms. Cancer, such as pancreatic ductal adenocarcinoma (PDAC), are often characterized by upregulation of membrane-bound proteins, such as MMP-14, that propagate survival integrin signaling. In order to target tumors, we have engineered an MMP-14 protease-activatable AAV vector that responds to both membrane-bound and extracellularly active MMPs. This "provector" was generated by inserting a tetra-aspartic acid inactivating motif flanked by the MMP-14 cleavage sequence IPESLRAG into the capsid subunits. The MMP-14 provector shows lower background transduction than previously developed provectors, leading to a 9.5-fold increase in transduction ability. In a murine model of PDAC, the MMP-14 provector shows increased delivery to an allograft tumor. This proof-of-concept study illustrates the possibilities of membrane-bound protease-activatable gene therapies to target tumors.
腺相关病毒（AAV）相对简单的结构使其易于构建成可控的递送平台。癌症，如胰腺导管腺癌（PDAC），通常的特征是膜结合蛋白（如MMP-14）上调，这些蛋白可促进存活整合素信号传导。为了靶向肿瘤，我们构建了一种MMP-14蛋白酶激活型AAV载体，它能对膜结合型和细胞外活性MMPs作出反应。这种“前载体”是通过将一个由MMP-14切割序列IPESLRAG侧翼的四聚天冬氨酸失活基序插入衣壳亚基而产生的。与先前开发的前载体相比，MMP-14前载体显示出更低的背景转导，导致转导能力提高了9.5倍。在PDAC小鼠模型中，MMP-14前载体显示出对同种异体移植肿瘤的递送增加。这项概念验证研究说明了膜结合蛋白酶激活型基因疗法靶向肿瘤的可能性。
