Clathrin-mediated Endocytosis and Subsequent Endo-Lysosomal Trafficking of Adeno-associated Virus/Phage

Stoneham, Charlotte A.; Hollinshead, Michael; Hajitou, Amin

doi:10.1074/jbc.m112.369389

Cited by 49 publications

(49 citation statements)

References 38 publications

(18 reference statements)

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“…Evaluating agents to increase transduction efficiency (37) or direct TNF-mediated signaling cascades toward induction of apoptosis (7) could be useful for maximizing the efficacy of AAVP-based therapy and overcoming these limitations related to viral gene delivery. Importantly, mice treated with Oct-AAVP-TNF also showed a significant increase in overall survival compared with mice treated with untargeted control AAVP (Fig.…”

Section: Oct-aavp-tnf Particles Target Pancreatic Neuroendocrine Tumomentioning

confidence: 99%

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

Smith

Yuan

Cardó-Vila

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.

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Section: Oct-aavp-tnf Particles Target Pancreatic Neuroendocrine Tumomentioning

confidence: 99%

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

Smith

Yuan

Cardó-Vila

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, genistein was reported to modulate the lysosomal metabolism [39]. Given that the endosomal-lysosomal pathway has been identified as an intracellular barrier to efficient transduction by RGD4C-AAVP [11], lysosomal alteration by genistein might facilitate RGD4C-AAVP escape from the lysosomes and subsequently higher nuclear accumulation of AAVP genome and enhanced gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…One reason could be associated with poor intracellular trafficking of the vector as RGD4C-AAVP is still a bacteria virus that has not evolved to deliver genes to mammalian cells. We have previously investigated the intracellular trafficking of RGD4C-AAVP in cancer cells and uncovered barriers to gene delivery by RGD4C-AAVP, such as weak phage attachment to the cell surface [10], poor endosomal escape [11], proteasome degradation [12] and nuclear transport (unpublished data). Proteasome inhibiting drugs and endosmolytic agents could be used to assist the phage to overcome intracellular barriers and subsequently enhance gene delivery.…”

Section: Introductionmentioning

confidence: 99%

The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction

et al. 2016

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Gene therapy has long been regarded as a promising treatment for cancer. However, cancer gene therapy is still facing the challenge of targeting gene delivery vectors specifically to tumors when administered via clinically acceptable non-invasive systemic routes (i.e. intravenous). The bacteria virus, bacteriophage (phage), represents a new generation of promising vectors in systemic gene delivery since their targeting can be achieved through phage capsid display ligands, which enable them to home to specific tumor receptors without the need to ablate any native eukaryotic tropism. We have previously reported a tumor specific bacteriophage vector named adeno-associated virus/phage, or AAVP, in which gene expression is under a recombinant human rAAV2 virus genome targeted to tumors via a ligand-directed phage capsid. However, cancer gene therapy with this tumor-targeted vector achieved variable outcomes ranging from tumor regression to no effect in both experimental and natural preclinical models. Herein, we hypothesized that combining the natural dietary genistein, with proven anticancer activity, would improve bacteriophage anticancer safe therapy. We show that combination treatment with genistein and AAVP increased targeted cancer cell killing by AAVP carrying the gene for Herpes simplex virus thymidine kinase (HSVtk) in 2D tissue cultures and 3D tumor spheroids. We found this increased tumor cell killing was associated with enhanced AAVP-mediated gene expression. Next, we established that genistein protects AAVP against proteasome degradation and enhances vector genome accumulation in the nucleus. Combination of genistein and phage-guided virotherapy is a safe and promising strategy that should be considered in anticancer therapy with AAVP.

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“…[22][23][24][25][26][27]52 Indeed, the addition of the RGD motif has long been seen as a way to enhance the cellular internalization of otherwise slowly internalizing nanosystems 26 and viruses. 53 In our hands, the same cyclic RGD peptide has been introduced previously to nanoliposomes and polyurethane-polyurea nanocapsules enhancing the internalization and the lysosomal localization of the nanosystem. 11, 30 Conjugation of c(RGDfk) to TMC is a simple procedure, and allows obtaining RGD-conjugated-PECs (PEC-RGD), without significant alterations of the particle average diameter and a slight decrease in ξ-potential value (Table 2) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 also maintaining average D and with a minor decrease in ξ-potential (Table 1).…”

Section: Specific Enzymatic Activity and Activity In Primary Culturesmentioning

confidence: 94%

Highly Versatile Polyelectrolyte Complexes for Improving the Enzyme Replacement Therapy of Lysosomal Storage Disorders

Giannotti

Abasolo

Oliva

et al. 2016

ACS Appl. Mater. Interfaces

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Clathrin-mediated Endocytosis and Subsequent Endo-Lysosomal Trafficking of Adeno-associated Virus/Phage

Cited by 49 publications

References 38 publications

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

The natural dietary genistein boosts bacteriophage-mediated cancer cell killing by improving phage-targeted tumor cell transduction

Highly Versatile Polyelectrolyte Complexes for Improving the Enzyme Replacement Therapy of Lysosomal Storage Disorders

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