Gene therapy benefits rare genetic disease patients

22 April 2015

Doctors have reported successful results from a pioneering gene therapy treatment of children with a rare genetic disease.

Wiskott-Aldrich Syndrome (WAS) is a severe form of genetic immune deficiency that causes extreme susceptibility to infections and reduced blood-clotting capacity. The condition, which affects between 1 and 10 children per million (mostly boys) is caused by mutations in the WAS gene and results in severe, repeated viral and bacterial infections, eczema, a range of autoimmune and inflammatory diseases and an increased risk of some forms of cancer, such as lymphoma. The only cure is a bone marrow transplant from a suitable tissue-matched donor, if available, without which affected children typically die by early adulthood.

A new gene therapy for the condition has been developed that uses a lentivirus-based vector to insert healthy, functional copies of the WAS gene into blood-cell precursors before transplantation into the bone marrow. Initial viral vectors were found to be effective treatments, but with an unacceptably high risk of insertional mutagenesis – cancer caused by the viral vector for the healthy genes inserting into the wrong place in the recipient cell’s genome. Newer vectors have been modified to reduce the probability of this happening.

An early trial showed promising results in young children with Wiskott-Aldrich Syndrome. Researchers at Great Ormond Street Hospital in London and Necker Children's Hospital in France went on to treat seven older children and young adults with severe forms of WAS, with their results just published in the journal JAMA .

Six out of the seven patients were still alive more than two years after treatment; the seventh died from a drug-resistant viral infection that was already present at the time of treatment. Of the six surviving patients, the characteristic eczema, recurrent infections and blood-clotting problems disappeared completely, and all those with autoimmune symptoms (five in all) showed improvement. Other forms of treatment (for example for blood-clotting and to prevent infections) were discontinued without ill-effect.

Genomic analysis also showed that the gene therapy vectors had behaved as expected. The authors note that longer follow-up of current patients and further trials with more patients are needed before firm conclusions can me made over long-term safety and efficacy of the treatment, but were cautiously optimistic. Prof Adrian Thrasher of the Great Ormond Street Hospital team told the BBC: "I think it is very significant, it is another clear and powerful demonstration that a gene therapy approach is an effective one”, adding that they hoped the therapeutic effect of treatment would prove to be long-lasting.

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