Gene therapy for immunodeficiency due to adenosine deaminase deficiency.

@article{Aiuti2009GeneTF,
  title={Gene therapy for immunodeficiency due to adenosine deaminase deficiency.},
  author={Alessandro Aiuti and Federica Cattaneo and Stefania Galimberti and Ulrike Benninghoff and Barbara Cassani and Luciano Callegaro and Samantha Scaramuzza and Grazia Andolfi and Massimiliano Mirolo and Immacolata Brigida and Antonella Tabucchi and Filippo Carlucci and Martha Marianne Eibl and Memet Aker and Shimon Slavin and Hamoud Al‐Mousa and Abdulaziz Al Ghonaium and Alina Ferster and Andrea Duppenthaler and Luigi Daniele Notarangelo and Uwe Wintergerst and Rebecca H Buckley and Marco Bregni and Sarah Marktel and Maria Grazia Valsecchi and Paolo Rossi and Fabio Ciceri and Roberto Miniero and Claudio Bordignon and Maria Grazia Roncarolo},
  journal={The New England journal of medicine},
  year={2009},
  volume={360 5},
  pages={
          447-58
        }
}
BACKGROUND We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. METHODS We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement… 

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References

SHOWING 1-10 OF 36 REFERENCES

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications.

The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease.

Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.

The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.

Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy.

There appears to be a quantitative relationship between residual ADA activity, determined by genotype, and both metabolic and clinical phenotype, and the major barrier to effective gene therapy remains the low efficiency of stem cell transduction with retroviral vectors.

Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.

Ex vivo gene therapy with gamma(c) can safely correct the immune deficiency of patients with X-linked severe combined immunodeficiency and allow patients to have a normal life.

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.

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.

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.

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.