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Efficiency of Protease-Activatable Virus Nanonodes Tuned Through Incorporation of Wild-Type Capsid Subunits

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Abstract

Virus nanonodes, a tunable multi-input protease-responsive gene delivery platform, was recently built by exploiting the self-assembly property of adeno-associated virus capsids. Upon detection of specific inputs (e.g., matrix metalloproteinases—MMPs), the engineered viruses output gene delivery to targeted cells. The first generation protease-activatable viruses (PAVs) displayed the desired protease-activated cellular receptor binding and transduction behaviors. However, the less than wild type (WT) level of gene delivery achieved by the prototype viruses has left room for improvement. In this report, we have devised a method to tackle this efficiency problem. Specifically, by controlling the ratio of WT to protease-activatable subunits in the assembled 60-mer virus capsid, we can easily increase the level of overall transduction achieved by the PAVs. Since a number of MMPs are overexpressed in a vast range of human pathologies, including cancer and cardiovascular disease, the protease-sensing viruses may find broad clinical use in future gene therapy applications.

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Acknowledgments

We would like to thank Shridhar Jayanthi for scientific discussions. The authors would like to acknowledge the University of North Carolina at Chapel Hill Gene Therapy Center Vector Core for providing us with pXX2, pXX6-80, and scAAV2-CMV-GFP. This material is based upon work supported by the National Science Foundation under Grant Number 0955536, Cancer Prevention Research Institute of Texas under grant number RP130455, and American Heart Association under grant number 13GRNT14420044 to J.S.

Conflict of interest

MLH, JJ, BEK, MY, FFW, JS declare that they have no conflicts of interest.

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No human studies or animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Department of Bioengineering, Rice University, Houston, TX, 77005, USA

    Michelle L. Ho, Justin Judd, Momona Yamagami, Fergus F. Wong & Junghae Suh

  2. Systems, Synthetic, and Physical Biology Program, Rice University, Houston, TX, 77005, USA

    Brianna E. Kuypers

Authors
  1. Michelle L. Ho
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  2. Justin Judd
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  3. Brianna E. Kuypers
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  4. Momona Yamagami
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  5. Fergus F. Wong
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  6. Junghae Suh
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Corresponding author

Correspondence to Junghae Suh.

Additional information

Associate Editor David Schaffer oversaw the review of this article.

This paper is part of the 2014 Young Innovators Issue.

Dr. Junghae Suh received her S.B. in Chemical Engineering at MIT and Ph.D. in Biomedical Engineering at Johns Hopkins School of Medicine. Before joining the Rice University department of Bioengineering as an assistant professor in 2007, she completed a two-year postdoctoral fellowship in the Laboratory of Genetics at the Salk Institute for Biological Studies. Her graduate research focused on understanding the interaction of nanoscale systems, either nature-derived or human-engineered, with complex biological environments in an effort to discover ruling paradigms that govern the performance of nanoparticles designed for biomedicine. Her postdoctoral research focused on studying how natural viruses interface with cellular machinery, particularly those that maintain homeostasis in the cell nucleus. Such studies should uncover new insights into how synthetic nanoparticle systems can be designed to yield the performance efficiencies rivaling that of viruses. Currently, Dr. Suh works at the interface of virology, biophysics, molecular biology, and protein engineering to investigate and create novel virus-based materials for various biomedical applications.

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Ho, M.L., Judd, J., Kuypers, B.E. et al. Efficiency of Protease-Activatable Virus Nanonodes Tuned Through Incorporation of Wild-Type Capsid Subunits. Cel. Mol. Bioeng. 7, 334–343 (2014). https://doi.org/10.1007/s12195-014-0334-y

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