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Gene Therapy. A Primer for Physicians.
  1. ALAN FRYER, Consultant clinical geneticist

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    Gene Therapy. A Primer for Physicians. 2nd Ed. By Kenneth W Culver. (Pp 198; hardback.) Mary Ann Liebert, 1996. ISBN 0-913113-25-5 .

    By 1995, over 1000 individuals had received experimental gene therapy treatment. The principles are clear—the gene of interest has to be identified, a delivery system developed, and the regulation of the expression of the gene has to be understood—for example our understanding of the control of the insulin and β-globin genes is incomplete and so gene therapy for diabetes and haemoglobinopathies is distant. The best candidates are disorders involving ‘housekeeping’ genes that do not require tight regulation of gene expression to match their function.

    Gene transfer can be performed in vitro whereby tissue of interest is removed from the body, altered genetically, and then returned to the patient. In vivo techniques involve direct gene transfer into the patient either as ‘naked DNA’ or in liposomes, viral vectors, or conjugated to a targeting structure such as an antibody to a specific cell surface moiety (receptor mediated gene transfer). This latter method holds considerable promise though no clinical trials have yet been performed.

    The ideal viral vector would allow efficient transfer of the gene into specific cells and then integrate the gene into the host cell’s genome so that it can be replicated—provided that the gene can be inserted at a specific site where there is no risk of mutagenesis. The virus should not induce an immune response, have no risk of becoming infectious, and be big enough to contain large human genes. Culver discusses the advantages and disadvantages of each of the current vectors.

    The above systems deal with inserting normal genes into cells but there are alternative strategies, for example repairing or blocking the function of a mutant gene. Repairing genes by homologous recombination has proved inefficient but a novel method is suggested whereby a disease causing point mutation is identified and an oligonucleotide synthesised that will bind adjacent to the mutation. A DNA damaging agent is added to the end of the oligonucleotide so that it is positioned next to the mutation. The mutated nucleotide is then damaged, activating normal DNA repair processes.

    Blocking the products of abnormal genes is an attractive proposition for dealing with ‘gain of function’ mutations. Oligonucleotides can be synthesised to bind to DNA or RNA sequences and prevent translation but so far the clinical application of this ‘antisense’ technology has been limited by inability to produce molecules with sufficient survival and duration of inhibitory effect.

    There are numerous possible applications of gene therapy in non-neoplastic disease. Expected advances may be most rapid in areas other than genetic disease—Culver predicts that the use of recombinant vaccines will be the most prevalent application of gene therapy over the next decade. Some ideas are futuristic, for example Culver considers the potential use of gene therapy in pain relief by transfer of ‘analgesic genes’, for example β-endorphin into sensory neurons in a neurotropic vector such as herpes simplex virus.

    The majority of gene therapy trials involve cancer treatment. Culver lists 15 strategies that are being considered and then illustrates them from current research.

    This is a readable and stimulating book which is geared to an American audience, listing all the current gene therapy trials in the USA and the biotechnology companies engaged in such research. It nevertheless provides a clear overview of the subject.

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