Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors

Susan S. Butler; Kenjiro Date; Takashi Okumura; Cooper Lueck; Bidyut Ghosh; Anirban Maitra; Junghae Suh

doi:10.1038/s41434-021-00255-9

Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors

Susan S. Butler, Kenjiro Date, Takashi Okumura, Cooper Lueck, Bidyut Ghosh, Anirban Maitra, Junghae Suh

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	138-146
Number of pages	9
Journal	Gene Therapy
Volume	29
Issue number	3-4
DOIs	https://doi.org/10.1038/s41434-021-00255-9
State	Published - Apr 2022

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

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title = "Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors",

abstract = "Adeno-associated virus{\textquoteright} (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.",

author = "Butler, {Susan S.} and Kenjiro Date and Takashi Okumura and Cooper Lueck and Bidyut Ghosh and Anirban Maitra and Junghae Suh",

note = "Funding Information: Funding NIH (R01CA207497) to JS, NCI MD Anderson/Rice Cancer T32 Fellowship 5T32CA196561-05 to SB, and NIH (R01CA220236 and R01CA218403) to A.M. Funding Information: We acknowledge University of North Carolina at Chapel Hill Gene Therapy Center Core for providing us with pXX6-80 and scAAV2-CMV-GFP, the University of Pennsylvania Vector Core for providing us with pAAV2/9, and the University of Iowa Vector Core for providing us with ITR-CMV-mCherry. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

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AU - Maitra, Anirban

AU - Suh, Junghae

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Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors

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