Delivery of disease responsive gene vectors with peptide targeted nanocomplexes

Stephen Hart (primary)
Child Health
University College London
David Gould (secondary)
Biochemical Pharmacology     
Queen Mary, University of London

Abstract

This project is a combination of gene therapy and nanotechnology with the aim of delivering gene therapeutics in a targeted and responsive manner. A PCR assembly approach will be used to generate synthetic promoters that are activated by the environment of inflammation through responsiveness to hypoxia and inflammatory mediators. As an alternative approach therapeutic molecules will be expressed from chemically-modified mRNA (cmRNA) which is a recently described non-viral vector. Mini circle DNA with responsive promoters and cmRNA will be delivered to target cells (synoviocytes and angiogenic endothelium) with peptide targeted nanocomplexes in vitro and in vivo in gene therapy studies.


References

  1. Mohamed H, Chernajovsky Y and Gould D. Assembly PCR synthesis of optimally designed, compact, multi-responsive promoters suited to gene therapy application. Sci Rep. 2016;6:29388. doi: 10.1038/srep29388.
  2. Adriaansen, J., Khoury, M., de Cortie, C. J., Fallaux, F. J., Bigey, P., Scherman, D., Gould, D. J., Chernajovsky, Y., Apparailly, F., Jorgensen, C., Vervoordeldonk, M. J., and Tak, P. P. (2007) Reduction of arthritis following intra-articular administration of an adeno-associated virus serotype 5 expressing a disease-inducible TNF-blocking agent. Ann Rheum Dis 66, 1143-1150.
  3. Grosse, S. M., Tagalakis, A. D., Mustapa, M. F., Elbs, M., Meng, Q. H., Mohammadi, A., Tabor, A. B., Hailes, H. C., and Hart, S. L. (2010) Tumor-specific gene transfer with receptor-mediated nanocomplexes modified by polyethylene glycol shielding and endosomally cleavable lipid and peptide linkers. FASEB J 24, 2301-2313.
  4. Tagalakis, A. D., Kenny, G. D., Bienemann, A. S., McCarthy, D., Munye, M. M., Taylor, H., Wyatt, M. J., Lythgoe, M. F., White, E. A., and Hart, S. L. (2014) PEGylation improves the receptor-mediated transfection efficiency of peptide-targeted, self-assembling, anionic nanocomplexes. J Control Release 174, 177-187.
  5. Kormann MSD, Hasenpusch G, Aneja MK, Nica G, Flemmer AW, Herber-Jonat S, Huppmann M, Mays LE, Illenyi M, Schams A, Griese M, Bittmann I, Handgretinger R, Hartl D, Rosenecker J, Rudolph C. (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotech 29, 154-157.

BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
Biotechnology
Techniques & Approaches
EngineeringImage ProcessingMicroscopy / ElectrophysiologyMolecular Biology