By Todd Neale, Staff Writer, MedPage Today
Published: January 28, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston. Earn CME/CE credit
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MILAN, Italy, Jan. 28 — A form of the rare “bubble boy disease” responds to gene therapy, with no long-term safety concerns, researchers said.
* Explain to interested patients that this study found that replacing a defective gene provided improvements in the immune systems of almost all of the children with severe combined immunodeficiency caused by lack of adenosine deaminase.
All 10 children who had severe combined immunodeficiency (SCID) caused by lack of adenosine deaminase were still alive a median of four years after the gene for the missing enzyme was replaced, Maria-Grazia Roncarolo, M.D., of the San Raffaele Telethon Institute for Gene Therapy here, and colleagues reported in the Jan. 29 issue of the New England Journal of Medicine.
None of the patients developed leukemia, which has been a serious side effect in previous gene therapy studies in patients with X-linked SCID.
“Gene therapy restored normal immune function in five patients and resulted in significant improvement in lymphocyte counts and functions in the other five patients, leading to protection from infectious complications,” the researchers said.
SCID due to a deficiency of adenosine deaminase is fatal if left untreated. In affected patients, the build-up of compounds the enzyme is meant to break down impairs the proliferation of lymphocytes, which leaves the patient vulnerable to infection.
It can be treated by a hematopoietic stem cell transplant from an HLA-identical sibling — the treatment of choice — or enzyme-replacement therapy, although both treatments have limitations, according to the researchers.
A transplant from a sibling is available for only a minority of patients and enzyme-replacement therapy often does not sustain the correction of the immunodeficiency, they said.
A promising avenue of research is the use of gene therapy, in which the missing gene is transferred by way of a retroviral vector into hematopoietic stem cells harvested from the patient’s bone marrow. The cells are then re-infused into the patient.
Dr. Roncarolo and colleagues tried this approach with 10 children (six girls and four boys) ranging in age from about seven months to 5.6 years. They first went through nonmyeloablative conditioning with the chemotherapeutic agent busulfan.
Four of the patients had undergone a failed bone marrow transplant from a mismatched related donor and six had had an inadequate response to enzyme-replacement therapy. One had been diagnosed at birth and had not yet undergone any treatments.
Nine of the patients had at least some degree of immune reconstitution with significant increases in T-cell counts at one year (P=0.004) and three years (P=0.03) and normalization of T-cell function, the researchers said.
At one year, 88% of T cells, 52.4% of B cells, and 59.2% of natural killer cells contained the previously deficient enzyme.
Through the end of follow-up ranging from 1.8 to 8.0 years, eight of the patients no longer needed enzyme-replacement therapy and did not show signs of defective detoxification of purine metabolites. The other two patients initiated replacement therapy after gene therapy, one at 4.8 months and one at 4.5 years.
Five patients had T-cell counts within the normal range and four had B-cell counts within normal range.
Five patients demonstrated antibody responses after exposure to vaccine or viral antigens.
In addition, the researchers said, “most patients had abnormalities in neuropsychomotor development at onset that improved during the follow-up period.”
“Effective protection against infections and improvement in physical development made a normal lifestyle possible,” the researchers said.
Serious adverse events included neutropenia lasting longer than 30 days in two patients, hypertension in one patient, central venous catheter-related infections in two patients, Epstein-Barr virus reactivation in one patient, and autoimmune hepatitis in one patient.
None of the patients developed leukemia, unlike the quarter of X-linked SCID patients who develop the malignancy after gene therapy.
Donald Kohn, M.D., of the University of Southern California and Children’s Hospital Los Angeles, and Fabio Candotti, M.D., of the National Human Genome Research Institute in Bethesda, Md., speculated in an accompanying editorial that this discrepancy “may reflect important biologic differences between the corrected hematopoietic stem cells in X-linked SCID and SCID due to adenosine deaminase deficiency.”
They pointed out that the protein coded by the gene responsible for X-linked SCID “provides a proliferation signal that may cooperate with the concomitantly deregulated expression of a proto-oncogene in proximity to the gene-transfer vector-integration site, favoring the establishment of malignant cells.”
Drs. Kohn and Candotti said that the outcomes of this and other gene therapy trials “are at least as good as, and arguably better than, the results reported for allogeneic transplantation,” and that studies should continue on gene therapy.
Similar and newer approaches may be used for the treatment of hemoglobinopathies, hemophilia, muscular dystrophy, congenital retinopathies, neurodegenerative disorders, and other genetic diseases, they said.
The study was supported by grants from the Italian Telethon Foundation, the Association Francaise contre les Myopathies-Telethon, the independent drug research program of the Italian Medicines Agency, and the European Commission.
One of Dr. Roncarolo’s co-authors, Claudio Bordignan, M.D., reported being the chief of the board and CEO of MolMed, which manufactured the vector and engineered cells used in the study. He left the study when he became CEO.
The editorialists reported no conflicts of interest.
Primary source: New England Journal of Medicine
Aiuti A, et al “Gene therapy for immunodeficiency due to adenosine deaminase deficiency” N Engl J Med 2009; 360: 447-458.
Additional source: New England Journal of Medicine
Kohn D, Candotti F “Gene therapy fulfilling its promise” N Engl J Med 2009; 360: 518-521.