Trials on gene therapy, which involves replacing, removing or introducing genes, for example, to produce a specific missing protein, were brought to a halt last year after French researchers reported a higher than expected number of cases of leukaemia among children being treated for the fatal 'baby-in-a-bubble' syndrome, severe combined immunodeficiency (X-SCID).
After three years of successful gene therapy for X-SCID, leukaemia occurred in the two youngest patients undergoing treatment. This news followed the death of a US patient after an inhaled adenoviral vector-delivered gene therapy led to an inflammatory response in the lungs.
But despite these setbacks, the first successful treatments have also been reported from clinical gene therapy studies.
Speaking at the third conference of Euregenethy, a Europe-funded network of scientists aiming to develop standardised gene therapy regulations and encourage discussions on related ethical issues, Alessandro Auiti from the San Raffaele Telethon Institute for Gene Therapy in Milano, Italy, reported that in patients suffering from the congenital immunodeficiency disease ADA-SCID (adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID)), a largely normal immune system has been restored by using genetically modified blood stem cells.
In some cases restoration lasted over a period of several years. Using retroviral vectors, a functional gene is transferred into stem cells from the patient's bone marrow as a replacement for the defective gene. The modified blood stem cells differentiate within the patient's body into normal blood cells thus improving immune functions.
"It is foreseeable that gene therapy will offer improved or novel therapies," noted Klaus Cichutek, vice president of the Paul-Ehrlich-Institut, near Frankfurt, which hosted the conference. "However, with increasing efficacy, we are also facing side effects. We have to learn how to balance these risks against the benefits for the patients and how to manage such risks."
To minimise risks as much as possible, a benefit/risk analysis is required in all cases, based on the exact knowledge of the individual gene therapy approach, Cichutek said. He added that in the trial on SCID-X1, two out of ten patients had developed leukaemia as an adverse reaction but after appropriate treatment they are alive. And according to current knowledge, the overall risk of this gene therapy is still lower than that of the available conventional therapy.
The leukaemia cases triggered by the SCID-X1 gene therapy were observed only in this special type of gene therapy. They were previously known only as a theoretical adverse reaction of retroviral vector use. The conference heard that Christof von Kalle at the University of Freiburg, Germany, is testing a special method for the early diagnosis of this adverse reaction.
"Adverse reactions must be communicated rapidly at an international level and must be evaluated by the scientific community by experts familiar with gene therapy," urged Euregenethy coordinator Odile Cohen-Haguenauer.
According to the group, the principal investigator of the SCID-X1 gene therapy study in Paris, Alain Fischer, has shown excellent conduct communicating internationally the clinical findings of his study and the subsequent investigations of the causes of the leukaemias observed.
Other highlights of the conference included reports on the clinical development of the gene therapy of rheumatoid arthritis by Barrie Carter, Targeted Genetics Corporation, Seattle, and reports by other scientists on gene therapy of cardiovascular disease and cancer as well as first trials of preventive vectored vaccines.
Another subject of discussion was the experience gained from the use of HIV-derived replication-incompetent gene transfer vectors. Inder Verma from The Salk Institute in La Jolla, California, reported on further development of lentiviral vectors. These vectors are replication-incompetent particles derived from the Human Immunodeficiency Virus or other related lentiviruses.
A study by Boro Dropulic, Virexsys, is currently underway in the USA using lentiviral vectors transferring HIV-inhibitory genes for the treatment of HIV-infected patients. The first three patients were treated without showing any adverse reactions. Lentiviral vectors are expected to improve gene transfer efficiency, thus improving ways of treating other severe diseases, such as cancer.
Researchers believe that so-called tumour suppressor genes could be used to suppress the replication of malignant cells. Inder Verma claimed that such vectors would bring about tremendous progress since they could also be used to modify resting cells which occur frequently in the body.