Strategies to improve non-viral vectors – potential applications in clinical transplantation

Abstract

Prevention of acute rejection has been well controlled with immunosuppressive drugs. However, the long-term control of rejection is less satisfactory and the side effects of chronic usage of these drugs are far from acceptable. Thus, more imaginative options for therapy need to be explored. Gene therapy has potential promise in preserving allografts, preventing rejection and inducing tolerance. Despite this initial promise in many animal models, the translation of gene therapy to the clinical arena has been slow. This may be related in part to the deficiencies in vector development. Existing viral vectors are efficient at transducing allografts, but they induce inflammatory and pathogenic effects. Although the alternative non-viral systems are relatively innocuous, they are less efficient at gene delivery. This review systematically analyses the limitations of non-viral vector technology and the strategies that have been developed to overcome these limitations. Future development of non-viral vectors may have potential application in clinical transplantation.

Keywords::

• dendrimers
• gene therapy
• immunology
• liposomes
• non-viral vectors
• polymers
• transplantation

Acknowledgements

PH Tan was funded by the Medical Research Council (London, England UK) and the Royal College of Surgeons, Edinburgh (Edinburgh, Scotland, UK) as a Clinical Research Training Fellow (2001 – 2004). Professor AJT George is a Research Development Fellow of the Biotechnology and Biological Sciences Research Council (Swindon, UK). Professor AJT George’s laboratory is funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, and the Roche Research Foundation (Basel, Switzerland). Due to space restrictions, only a fraction of the relevant literature was cited, and the authors apologise to any colleagues whose contributions may not be appropriately acknowledged in this review.

Notes

sCD2/18/40/48: Soluble CD2/18/40/48; sICAM: Soluble intercellular adhesion molecule; sIL-1 R: Soluble interleukin-1 receptor; sLFA: Soluble leukocyte function-associated antigen; sSelectin: Soluble selectin; sTNF-α R: Soluble tumour necrosis factor-α receptor; sTRAIL: Soluble TNF-related apoptosis-inducing ligand; sVCAM: Soluble vascular cell adhesion molecule.

In the genetic manipulation of allografts, the possible pathways that can be blocked or modulated are summarised in this box. CTLA4–Ig: Cytotoxic T cell leukocyte antigen-4 immunoglobulin; FasL: Fas ligand; IDO: Indoleamine 2-3 dioxygenase; IL-1 Rα: interleukin-1 receptor α; sCD40 Ig: Soluble CD40 immunoglobulin; sICAM: Soluble intercellular adhesion molecule; sIFN-γ R: Soluble interferon-γ receptor; sIL-1 R: Soluble interleukin-1 receptor; sTNF-α R: Soluble tumour necrosis factor-α receptor; TGF-β: Transforming growth factor-β; vIL-10: Viral interleukin-10.

The therapeutic genes that could be used to generate tolerogenic antigen-presenting cells are summarised. CTLA4–Ig: Cytotoxic T cell leukocyte antigen-4 immunoglobulin; CTLA4–KDEL: Fusion protein of cytotoxic T cell leukocyte antigen-4 with KDEL amino acid sequence; FasL; Fas ligand; IDO: Indoleamine 2-3 dioxygenase; sICAM-1: Soluble intercellular adhesion molecule; TGF-β: Transformation growth factor-β; TRAIL: Tumour necrosis factor-related apoptosis-inducing ligand; vIL-10: Viral interleukin-10.

This box summarises the potential steps by which one can improve the shortcomings of non-viral vectors so that they can be fully utilised in clinical transplantation.