Prospects for gene therapy


Gene therapy refers to the transfer of exogenous DNA into cells in order to combat disease by modifying gene expression. Such modifications may benefit the cell directly, or may modulate disease activity elsewhere by altering protein secretion by that cell. It should be noted that for ethical purposes, the principle of gene therapy into cells contributing to the germ line has not been accepted; instead, the aim is to offer specific treatment to each individual (and not their descendants by default) by transferring DNA into non-germ line 'somatic' cells.

Monogenic diseases such as adenosine deaminase (ADA) deficiency (see below) and cystic fibrosis were the first to be tackled, providing an active gene where both copies of the endogenous genes had been inactivated by inherited mutations. The current trend is aimed at polygenic disease. Cancer is a major target for gene therapy, with the aim, for example, of transferring 'suicide genes' into cancer cells. The earlier discussions catalogued the ability of molecular techniques to cut and reanneal adjacent pieces of DNA, and to alter DNA sequence, and the use of such modified nucleic acids to produce genetically engineered animals. Such descriptions might make it appear that the concept of gene therapy will be realised easily. Unfortunately, this is not the case. Of more than 200 gene therapy trials to date, there has not been one unqualified success, possibly reflecting an over-eagerness to rush to clinical trials.

Outlines current gene therapy strategies. Naked DNA may be transferred to a cell, but successful delivery is rare. Some improvement is obtained by transferring the DNA in a liposome with a lipid coat, but viral-based vectors, either non-integrative such as adeno- and herpes simplex viruses, or integrative such as retro- and lentiviruses, lead to marked improvements in delivery. Furthermore, a virus which selectively infects a particular cell type may be chosen. However, the use of viruses generates additional problems. For example, adenoviral vectors are more likely to stimulate a significant immune response, and integrative viruses carry the risk of insertional mutagenesis. The development of new and improved naturally occurring or synthetic vectors is a current priority for research, and the field is advancing rapidly.

The paradigm of adenosine deaminase (ADA) deficiency

This was the first disease for which gene therapy was attempted. In ADA deficiency, inheritance of mutations in both copies of the gene resulting in ADA activity of less than 5% of normal leads to severe combined immunodeficiency (SCID) due to lack of ADA in lymphocytes. Factors in favour of gene therapy success

  • Efficient DNA delivery into cells
  • Persistent and sufficient DNA expression
  • Persistence of the infected cell and its progeny in the face of cellular lifespan and host immune responses
  • Efficacy of transferred genetic material in correcting disease
  • Safety in view of:
  • Unknown effects of long-term expression of foreign genes Irreversible integration of foreign DNA (retroviruses)
Some current and future targets
  • Replacement of defective inherited gene Adenosine deaminase (ADA) deficiency Cystic fibrosis
  • Local transfer for acquired disease Angioplasty-associated re-stenosis (VEGF) Cancer cells (e.g. p53 transfer)

were that lymphocytes were readily a ccessible, and that it was known that for clinical effectiveness, improvement of enzyme activity of even 1-2% could be sufficient to delay immunodeficiency for months or even years. However, current gene therapy approaches, while well tolerated, have yet to result in a sufficient increase in ADA activity to allow withdrawal of enzyme replacement therapy.