Nature Genetics pp 245 - 250 and pp 206 - 208

Cancer is caused by cells growing out of control; perturbations of pathways involved in growth and development are found in both familial and sporadic cancers. The Wnt/wingless signalling pathway, which influences the body plan of the developing embryo, is a classic example. The pathway is activated by Wnt factors binding to receptors at the cell surface - this signal causes beta-catenin to accumulate and move to the nucleus, where it activates the expression of other genes. The activity of beta-catenin is kept in check by various proteins, including APC. Several components of the Wnt pathway are disrupted in human cancers: loss of APC function causes inherited and sporadic cases of colorectal cancer, and abnormal increases in the levels of beta-catenin lead to liver cancer.

Yusuke Nakamura and colleagues (University of Tokyo) now report that another component of the Wnt pathway called axin - which, like APC, is a negative regulator of beta-catenin - is disrupted in liver cancer. The researchers went on to show that introducing intact axin into liver tumour cells deficient in axin triggered programmed death in these cancerous cells. Using a similar approach, they found they could also kill colon cancer cells that have intact axin but have accumulated excess beta-catenin, indicating that increasing the levels of axin might be a therapeutic means to eliminate a variety of tumours. Hans Clevers (University Hospital, Netherlands), an expert on Wnt signalling in development and cancer, discusses the findings in an accompanying News & Views article.

Nature Genetics pp 257 - 261 and pp 201 - 202

The main challenge for gene therapists is to develop gene-delivery vehicles (called vectors) that allow safe and efficacious introduction of a therapeutic gene into patients. Katherine High (The Children's Hospital of Philadelphia), Mark Kay (Stanford University School of Medicine) and colleagues have spent the past six years developing gene therapy vectors - based on the adeno-associated virus (AAV) - for treating haemophilia. But before testing in humans, therapeutic vectors must be evaluated in suitable animal models. High and coworkers tested their AAV vectors, carrying the gene encoding factor IX, in mouse and dog models of haemophilia. Their pre-clinical studies suggested that the treatment was safe and improved the disease state, so High and co-workers initiated a human gene therapy trial using these vectors to treat haemophilia B. They now report encouraging results from an early stage of this trial.

Three patients participated in a so-called 'phase-I clinical trial', which aims to determine the safety of a given treatment. To the investigators' surprise, they saw modest but measurable improvement in two of the patients injected with very low levels of AAV. Based on earlier studies in animal models, this low dose was not expected to make a difference. The amount of factor IX, a blood-clotting factor, was slightly increased and both patients reported that their need to self-administer factor IX was reduced.

As with most phase-I trials, this study is designed to have dose-escalation; the first three patients were injected with a very low dose, and subsequent groups will receive progressively higher doses. The results reported by High and colleagues are encouraging and, if confirmed - by demonstration of improved efficacy, without toxicity, in a large number of patients injected with higher doses - have the potential to become one of the first studies to show safety and efficacy of gene therapy for an inherited human disease.

The editorial in the same issue discusses this study as well as some of the difficult issues surrounding gene therapy and other clinical trials, such as informed consent and insurance coverage.

Nature Genetics pp 287 - 290

Humans and other mammals don't have to remember to breathe. A respiratory centre in the brain coordinates how often and how deeply we breathe in order to provide the body with enough oxygen. Inherited and acquired defects in this circuitry have serious consequences. Congenital central hypoventilation syndrome, for example, causes life-threatening hypoxia (shortage of oxygen) soon after birth. Stanley Korsmeyer (Harvard Medical School) and colleagues have generated mutant mice that show similar defects: pups don't inhale deeply enough, have frequent periods in which they don't breathe at all (called apnoeas), and all of them die from central respiratory failure within 24 hours after birth. The mutant mice lack the Rnx gene, which is expressed in the ventral medulla of the developing brain, an area known to house the respiratory centre. This study identifies the first gene to regulate the prenatal development of a respiratory control centre in the brain.