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

  title={Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning},
  author={Alessandro Aiuti and Shimon Slavin and Memet Aker and Francesca Ficara and Sara Deola and Alessandra Mortellaro and Shoshana Morecki and Grazia Andolfi and Antonella Tabucchi and Filippo Carlucci and Enrico Marinello and Federica Cattaneo and Sergio Vai and Paolo Servida and Roberto Miniero and Maria Grazia Roncarolo and Claudio Bordignon},
  pages={2410 - 2413}
Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)–deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed the effect of gene therapy alone to be evaluated… 

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.

Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning.

A Tale of Two SCIDs

Two new reports in this issue of Science Translational Medicine add to the accumulating findings from gene therapy trials in Italy, France, and the United States that show clinical benefits of this alternative treatment.

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.

Treating Immunodeficiency through HSC Gene Therapy.

Immunoresponse to Gene-Modified Hematopoietic Stem Cells

Gene Therapy for Primary Immunodeficiencies

Clinical trials for SCID-X1, Wiskott-Aldrich syndrome, and recently ADA-SCID showed sustained engraftment of gene-corrected cells, restored immune function, and general improvement of clinical condition, with a positive safety profile, so continuous monitoring will be important to confirm long-term safety and efficacy.

Ten years of gene therapy for primary immune deficiencies.

  • A. AiutiM. Roncarolo
  • Medicine, Biology
    Hematology. American Society of Hematology. Education Program
  • 2009
Following recent advances in preclinical studies, lentiviral vectors are now being translated into new clinical approaches, such as Wiskott-Aldrich Syndrome, and will provide significant advantages in terms of natural gene regulation and reduction in the potential for adverse mutagenic events.

Gene therapy of chronic granulomatous disease: the engraftment dilemma.

This review summarizes the data from clinical trials for chronic granulomatous disease (CGD) and provides some insights into treatment options that may lead to a successful application of gene therapy for CGD.

Gene Therapy for SCID

This work reports that SCID-X1 and adenosine deaminase SCID have been successfully treated with hematopoietic stem cell gene therapy (HSC-GT) and patients show impressive levels of immune reconstitution.



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

It is concluded here that gene therapy can be a safe and effective addition to treatment for some patients with this severe immunodeficiency disease.

Transfer of the ADA gene into bone marrow cells and peripheral blood lymphocytes for the treatment of patients affected by ADA-deficient SCID.

Experiments in vitro and in vivo have documented that T-lymphocytes are suitable vehicles for gene transfer and the selective engraftment of T-cells only, following bone marrow transplantation, has resulted in reconstitution of cellular and humoral immunity.

Bone marrow gene transfer in three patients with adenosine deaminase deficiency.

It is hypothesize that lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relative low numbers in the patients with ADA deficiency.

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.

Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.

A gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective gammac Moloney retrovirus-derived vector and ex vivo infection of CD34+ cells, which provided full correction of disease phenotype and clinical benefit.

Gene Therapy in Peripheral Blood Lymphocytes and Bone Marrow for ADA− Immunodeficient Patients

Results indicate successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny.

Engraftment of gene–modified umbilical cord blood cells in neonates with adenosine deaminase deficiency

The continued presence and expression of the introduced gene in leukocytes from bone marrow and peripheral blood for 18 months demonstrates that umbilical cord blood cells may be genetically modified with retroviral vectors and engrafted in neonates for gene therapy.

Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

Transplantation of marrow from a related donor is a life-saving and life-sustaining treatment for patients with any type of severe combined immunodeficiency, even when there is no HLA-identical donor.

Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease.

  • H. MalechP. Maples J. Gallin
  • Medicine, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
This trial piloted the use of animal protein-free medium and a blood-bank-compatible closed system of gas-permeable plastic containers for culture and transduction of the PBSCs and found that these features enhance the safety of PBSCs directed gene therapy.

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.