BioWorld International Correspondent
PARIS - A gene therapy trial being conducted at the Necker children's hospital in Paris has been put on hold after one subject developed a serious complication.
The therapy was being tested to treat severe combined immune deficiency linked to the X chromosome, SCID-X1, a very rare genetic disease with which some babies are born. SCID-X1 is characterized by the organism's inability to generate T lymphocytes, thus depriving it of a viable defense against infection. It is caused by the faulty expression or function of a protein called gamma-c, which acts as a receptor of signals needed for the differentiation of cells that are precursors of lymphocytes.
Without treatment, the disease results in death within a year of birth. Up to now, the only available treatment has been the transplant of bone marrow from a family member who ideally shares the same tissular antigens of HLA histocompatibility, but that is possible in only 20 percent of cases.
The gene therapy entails the ex vivo transfer of a normal copy of the gamma-c gene into medullar cells taken from the patient and reintroduction using a viral vector. It was developed by researchers at the French National Institute of Health and Medical Research (INSERM) with the support of the French Muscular Dystrophy Association.
The Phase I/II trial at the Necker hospital, part of the Paris public hospital authority, began in March 1999, and 10 subjects have since been treated. They included nine babies suffering from a complete absence of T lymphocytes. Eight of them developed an effective immune system after acquiring the ability to generate T lymphocytes, enabling them to lead a normal life. In one of them, the therapy failed because the treated cells became trapped in the spleen.
No adverse side effect was observed in any of the patients until the spring of this year, when one of the subjects, who was treated in October 1999, was found to have too many of a particular population of T lymphocytes in his blood. The chief investigator, Alain Fischer, told BioWorld International that the decision to suspend the trial was made in August, when the proliferation of unwanted lymphocytes reached a disturbingly high level.
After being duly informed, the regulatory agency responsible, the French Agency for the Safety and Hygiene of Health Products (AFSSPS), has now issued a statement explaining that an analysis of the cells concerned revealed that they were monoclonal in nature and that the insertion of the provirus (a DNA copy of the genetic material of the virus vector utilized) into the genome had caused the deregulation of the expression of a cellular gene.
Describing the event, called insertional mutagenesis, as a known but "very slight" risk in gene therapies that use retroviral vectors, the AFSSPS said the patient's cell proliferation problem was being treated and that further investigations were being conducted to determine the precise proliferation mechanism.
Fischer stressed that it was only a temporary suspension while further studies were carried out to determine how to proceed. He said that, in any case, there was no question of moving onto a Phase III trial, since the extreme rarity of the disease meant there were too few patients for such an exercise. There are only five cases a year in France, for instance. He added that there are plans for extending the therapy to other similar and rare pathologies in the future.