Questions linger about unexplained gene-therapy trial death

Gene therapists are waiting nervously for the outcome of investigations into the death of a participant in a pioneering gene therapy trial in Germany, expected in the next few weeks. One of three individuals enrolled in the trial, set to treat the rare but life-threatening immunodeficiency disease chronic granulomatous disease (CGD), died on 10 April after his colon perforated and consequent septic shock caused organ failure. Scientists reported the death at the annual meeting of the German Society of Internal Medicine on 26 April, adding that an investigation into the exact cause of death is ongoing. "The worst-case scenario would be that we never resolve what actually caused the death," says Harry Malech, a gene therapist at the US National Institutes of Health. "Then we will all be left with uncertainty." CGD, whose victims suffer incessant infections, is caused by a defective gp91phox gene, which prevents normal maturation of leukocytes, a type of immune cell. The therapy involved using a retroviral vector to insert a replacement gene into blood stem cells. The cells of the trial participant who died had successfully incorporated the gene and, at least in the first 16 months after therapy, the gene appeared to be functioning. Cells with the gene were able to kill infections in vitro (Nat. Med. 12, 401–409; 2006). That individual underwent gene therapy in January 2004 and enjoyed a life without hospitalization until late 2005. The others—one treated in Frankfurt in May 2004 and the other in Zurich in May 2005—are also progressing without severe infections. The trial investigators have already ruled out any leukemia-like diseases such as those seen in 2003 and 2004 in gene therapy trials for the so-called 'bubble boy disease.' "The death was definitely not a direct consequence of the transferred gene," says Manual Grez, the molecular virologist who led the CGD trial. But an indirect effect cannot be ruled out until the investigation is finished. The researchers are trying to determine the number of gene-modified immune cells to see if they have fallen below levels required to fight infections. And they are testing to see whether the transferred gene has stopped functioning efficiently. They are also trying to identify the kind of infections in the trial participants. Some infections, such as with the bacterium Borkhalderia cepacia, are unique to CDG, notes Malech, and its presence would be an indication that the death was a result of underlying disease that the therapy had failed to cure. Regulatory bodies have not halted gene therapy trials as a result of the death, but recruitment into the Frankfurt trial is temporarily suspended. Malech has also put on hold his plans to apply for permission to conduct similar trials at the US National Institutes of Health. "Source":[ http://www.nature.com/nm/journal/v12/n6/full/nm0606-597a.html]

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