Open AccessMembrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors
Author(s) -
Susan Butler,
Kenjiro Date,
Takashi Okumura,
Cooper Lueck,
Bidyut Ghosh,
Anirban Maitra,
Junghae Suh
Publication year - 2021
Publication title -
gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.332
H-Index - 159
eISSN - 1476-5462
pISSN - 0969-7128
DOI - 10.1038/s41434-021-00255-9
Subject(s) - biology , transduction (biophysics) , gene delivery , adeno associated virus , rgd motif , matrix metalloproteinase , genetic enhancement , pancreatic cancer , capsid , protease , cancer research , viral vector , microbiology and biotechnology , virology , integrin , gene , virus , recombinant dna , enzyme , cancer , biochemistry , vector (molecular biology) , cell , genetics
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.