1. ESRC Genomics Network (archive)
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  3. The Human Genre Project

Egenis · News

Targeted Gene Editing In Vivo



In a recent publication (Lolle et al Nature 434,505-509,2005) scientists reported the unexpected finding that in their experimental plants an altered or damaged DNA script can be edited and corrected by reference to a template ( representing the unaltered script) which is not located within the plant’s own genome (i.e. not acquired from its parents) but seems rather to have been acquired directly from its grand parents most likely in the form of RNA.

This remarkable example of self repair and all that it means for our post-Mendelian expectations is now, in a sense, mirrored in a report that another group of scientists working at Sangamo Biosciences USA (Nature News April 3 rd). They, using a sophisticated set of engineered enzymic tools plus a corrective template of their own making have been able to intervene in human cells to edit and correct a specific DNA sequence alteration corresponding to a severe inherited disease.

The ability to target specifically the stretch of DNA containing the alteration is invested in a set of proteins called zinc finger proteins which are capable of accessing DNA within chromatin, recognising and binding to specific short DNA motifs. These proteins are a part of the normal set of regulatory mechanisms which act within the genome. By splicing several of such proteins together in different permutations it is possible to construct reagents capable of binding to longer specific DNA sequences and, by adding a further enzyme capable of cutting DNA, agents can be obtained which can cut DNA at these sequences. The broken sequence acts as a stimulus for recruitment of a set of repair enzymes which together with the corrective template supplied along with the zinc finger agent can effect repair of the altered sequence. The Sangamo group observed a high frequency of repair (18%) among treated cells. Potentially many of the 4,000 or so monogenic heritable disorders for which sequence data are available could be targeted for repair in this way.

In its eloquent precision and simplicity this technology could provide an alternative to the current methods employed in human gene therapy with their dependence on delivery vectors based on retroviruses and consequent uncontrolled insertion within the genome. In this light it might be recalled that some past attempts at providing gene therapy for X-SCID (severe combined immunodeficiency disease) resulted in severe vector/insertion–specific side effects like leukaemia. This form of zinc finger-mediated targeted sequence editing involves no treatment with recombinant DNA or vectors and leaves no footprint in the genome save the repaired sequence. In fact it may be inappropriate to bracket this technology with gene therapy at all since the zinc finger agent merely points the normal genomic mechanisms of repair and recombination to a specific site. Genomic therapy might be a better term.

The technology cannot yet be used to treat cells within the body but should be applicable to stem cells which could then be used to repopulate the body. We may expect early applications to involve diseases specific to blood cells and their precursors, the examples quoted by Sangamo being the treatment of immune cells to repair the afore-mentioned X-SCID or to innactivate HIV receptors.

Whether the apparent tidiness of zinc finger technology triggers its widespread application or its application to more pluripotent stem cells or even embryos remains to be seen. If it does we can expect a strong resurgence of the questions surrounding the geneticisation of medicine : what is a disorder?; who defines disorder?; which disorders should be treated and who should decide?; who will invest in developing the specific tool for each treatment?.

The other more tantalizing question is how far might the technology be able to go in generating precise and heritable changes in the genomes of other species e.g. plants?