T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years

  title={T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years},
  author={R. Michael Blaese and Kenneth W. Culver and A Dusty Miller and Charles S. Carter and Thomas A. Fleisher and Mario Clerici and Gene M. Shearer and Lauren Chang and Yawen L. Chiang and Paul Tolstoshev and Jay J. Greenblatt and Steven A. Rosenberg and H Klein and Mel Berger and Craig A. Mullen and W. J. Ramsey and Linda Mesler Muul and Richard A. Morgan and W. French Anderson},
  pages={475 - 480}
In 1990, a clinical trial was started using retroviral-mediated transfer of the adenosine deaminase (ADA) gene into the T cells of two children with severe combined immunodeficiency (ADA− SCID). The number of blood T cells normalized as did many cellular and humoral immune responses. Gene treatment ended after 2 years, but integrated vector and ADA gene expression in T cells persisted. Although many components remain to be perfected, it is concluded here that gene therapy can be a safe and… 


Development of gene therapy: potential in severe combined immunodeficiency due to adenosine deaminase deficiency

The developments achieved in over two decades of clinical and laboratory research that led to the establishment of a protocol for the autologous transplant of retroviral vector-mediated gene-modified hematopoietic stem cells are discussed.

Gene Therapy for Severe Combined Immunodeficiency Caused by Adenosine Deaminase Deficiency: Improved Retroviral Vectors for Clinical Trials

This chapter reviews several crucial problems inherent in the current retroviral technology based on the clinical data observed in these pioneering ADA gene therapy trials and presents the new Retroviral vector system for the next stem cell gene therapy.

Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning

Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions, and lower toxic metabolites, indicating the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID.

Hematopoietic stem cell gene therapy for adenosine deaminase deficient-SCID

Stem cell gene therapy combined with appropriate conditioning regimens might be extended to other genetic disorders of the hematopoietic system.

Gene Therapy Approaches to Immunodeficiency.

Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency.

The results obtained in this trial are in agreement with previously published observations and support the usefulness of T lymphocyte-directed gene transfer in the treatment of ADA-SCID.

Gene therapy for immunodeficiency due to adenosine deaminase deficiency.

Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency and effective protection against infections and improvement in physical development made a normal lifestyle possible.

Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency

In comparison with SCID-X1, ADA-SCID gene therapy presents a better safety profile and engraftment of multilineage transduced stem/progenitor cells, thanks to the use of nonmyeloablative preconditioning.

T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates

Despite the long-term engraftment of transduced stem cells and selective accumulation of gene-containing T lymphocytes, improved gene transfer and expression will be needed to attain a therapeutic effect inenosine deaminase-deficient severe combined immunodeficiency.



Lymphocyte gene therapy.

Monthly injections of genetically corrected ADA-corrected T cells have resulted in measurable ADA activity in the peripheral blood and the in vivo production of antibody to blood group antigen.

An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency.

Retroviral vector gene transfer is necessary and sufficient for development of specific immune functions in vivo and has therapeutic potential to correct this lethal immunodeficiency.

Lymphocytes as cellular vehicles for gene therapy in mouse and man.

A portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency is provided.

Antibody responses to bacteriophage phi X174 in patients with adenosine deaminase deficiency.

Assessment of antibody responses to immunization with bacteriophage phi X174 is a useful method to monitor humoral immune function in treated ADA-deficient patients and can be used to estimate when intravenous immunoglobulin (IVIG) prophylaxis may be safely discontinued.

Correction of adenosine deaminase deficiency in cultured human T and B cells by retrovirus-mediated gene transfer.

  • P. KantoffD. Kohn J. Hutton
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1986
Results support the suggestion that retroviral vector gene-delivery systems show promise for application to human gene therapy and reverse the hypersensitivity of genetically deficient lymphocytes to 2'-deoxyadenosine toxicity.

Suppression of an antibody to adenosine-deaminase (ADA) in an ADA-deficient patient receiving polyethylene glycol modified adenosine deaminase.

An adenosine deaminase (ADA) deficient patient with severe combined immunodeficiency (SCID) developed resistance to therapeutic injections of bovine ADA conjugated to polyethylene glycol (PEG-ADA) with sustained clinical and immunologic improvement, including weakly positive antigen-specific T cell proliferative responses to tetanus and Candida.

Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency.

Frozen irradiated plasma, which alone had no effect on lymphocytes numbers or responses, promoted lymphocytosis when given with frozen irradiated red blood cells, suggesting enzyme replacement therapy may provide a way to treat patients with adenosine deaminase deficiency associated with severe combined immunodeficiency disease who do not have histocompatible bone-marrow donors.

Enzyme Replacement Therapy with Polyethylene Glycol-Adenosine Deaminase in Adenosine Deaminase Deficiency: Overview and Case Reports of Three Patients, Including Two Now Receiving Gene Therapy

Recovery of specific immune function during treatment with PEG-ADA is illustrated for three patients, who represent early, delayed, and late onset of immunodeficiency disease.

Gene transfer into humans--immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction.

These studies demonstrate the feasibility and safety of using retroviral gene transduction for human gene therapy and have implications for the design of TIL with improved antitumor potency, as well as for the possible use of lymphocytes for the gene therapy of other diseases.