Gene therapy promises many new ways to combat disease. The best strategy depends on the disease, but two important goals are that the genetic change is precise, and that gene expression is controlled according to physiological needs. Two new studies report progress towards both of these aims.

For inherited diseases, precise correction of the causative mutation could be achieved by homologous recombination. The best opportunities for this are afforded by diseases of the haematopoietic system. Haematopoietic stem cells (HSCs) can be harvested from a patient, modified ex vivo, and transfused back into the patient. Hatada et al. isolated bone marrow cells from Hprt -deficient mice (a model for Lesch-Nyhan syndrome), and corrected the Hprt gene by homologous recombination at a frequency similar to that achieved in embryonic stem cells. Although the corrected cells are haematopoietic progenitor cells — not HSCs — the results will encourage further efforts to modify HSCs by homologous recombination.

In the case of a more complex multifactorial disease such as diabetes, gene therapy can offer a different approach to disease treatment. The key problem in type I diabetes sufferers is a lack of insulin. The production of insulin is regulated in response to glucose, so combatting diabetes using gene therapy requires an expression system that is regulable in vivo. Lee and colleagues created an insulin expression vector containing a glucose-regulable promoter. The vector corrected insulin deficiency in rat and mouse models for type I diabetes for at least several months after vector transduction and reproduced the physiological coordination of insulin levels with those of glucose. There are some important questions to consider before a similar approach can be contemplated in humans but, as in the study by Hatada et al., Lee et al. have shown how gene-therapy technology can be improved to bring precision and control a little closer.

Update — note added in proof Glucose-dependent insulin release from genetically engineered K cells. Cheung, A. T. et al. Science 290, 1959-1962 (2000) Pubmed

A recent paper in Science reports a second glucose-responsive system for tackling diabetes. Cheung et al. constructed a transgene comprising the human insulin gene and the control region of the glucose-dependent insulinotropic polypeptide (GIP). GIP is expressed in specialized, glucose-responsive gut cells, known as K cells, with kinetics that are very similar to insulin expression. The insulin transgene was expressed in K cells of transgenic mice in a glucose-dependent fashion. Notably, the transgene could rescue the diabetic phenotype of a chemically induced mouse diabetes model.