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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-09-2800.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2563-2569
GENE THERAPY
Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term
results of the first clinical gene therapy trial
Linda Mesler Muul,
Laura M. Tuschong,
Sherry Lau Soenen,
G. Jayashree Jagadeesh,
W. Jay Ramsey,
Zhifeng Long,
Charles S. Carter,
Elizabeth K. Garabedian,
Melinna Alleyne,
Margaret Brown,
Wendy Bernstein,
Shepherd H. Schurman,
Thomas A. Fleisher,
Susan F. Leitman,
Cynthia E. Dunbar,
R. Michael Blaese, and
Fabio Candotti
From the Clinical Gene Therapy Branch, Genetics
and Molecular Biology Branch, Medical Genetics Branch, National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD;
Genetic Therapy, Gaithersburg MD; Department of Transfusion Medicine,
Clinical Center, National Institutes of Health, Bethesda, MD;
Department of Laboratory Medicine, Clinical Center, National Institutes
of Health, Bethesda, MD; Walter Reed Army Medical Center, Washington,
DC; Hematology Branch, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD; and Fund for
Inherited Disease Research, Newtown, PA.
The first human gene therapy experiment begun in September 1990 used a retroviral vector containing the human adenosine deaminase (ADA)
cDNA to transduce mature peripheral blood lymphocytes from patients
with ADA deficiency, an inherited disorder of immunity. Two patients
who had been treated with intramuscular injections of pegylated bovine
ADA (PEG-ADA) for 2 to 4 years were enrolled in this trial and each
received a total of approximately 1011 cells in 11 or 12 infusions over a period of about 2 years. No adverse events were
observed. During and after treatment, the patients continued to receive
PEG-ADA, although at a reduced dose. Ten years after the last cell
infusion, approximately 20% of the first patient's lymphocytes still
carry and express the retroviral gene, indicating that the effects of
gene transfer can be remarkably long lasting. On the contrary, the
persistence of gene-marked cells is very low (< 0.1%), and no
expression of the transgene is detectable in lymphocytes from the
second patient who developed persisting antibodies to components of the
gene transfer system. Data collected from these original patients have
provided novel information about the longevity of T lymphocytes in
humans and persistence of gene expression in vivo from vectors driven
by the Moloney murine leukemia virus long-terminal repeat (LTR)
promoter. This long-term follow-up has also provided unique evidence
supporting the safety of retroviral-mediated gene transfer and
illustrates clear examples of both the potential and the pitfalls of
gene therapy in humans.
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