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 A 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… Expand

Paper Mentions

Interventional Clinical Trial
This is phase I/II protocol to evaluate the safety and efficacy of WAS gene transfer into hematopoietic stem/progenitor cells for the treatment of Wiskott Aldrich Syndrome.  
ConditionsWiskott-Aldrich Syndrome (WAS)
InterventionGenetic
Interventional Clinical Trial
This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin… Expand
ConditionsBeta-Thalassemia
InterventionGenetic
Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency.
TLDR
This investigation investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Expand
Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency
TLDR
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. Expand
Gene Therapy for Primary Immunodeficiencies: Current Status and Future Prospects
TLDR
This review details gene therapy trials for X-linked and adenosine deaminase-deficient severe combined immunodeficiency (SCID), Wiskott–Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Expand
Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.
TLDR
The studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency. Expand
Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety
TLDR
Gene therapy with an autologous CD34+-enriched cell fraction that containsCD34+ cells transduced with a retroviral vector encoding the human ADA cDNA sequence leads to immune reconstitution in most patients and did not impact the incidence of neurologic/hearing impairments. Expand
Efficacy of gene therapy for X-linked severe combined immunodeficiency.
TLDR
After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1 and may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. Expand
Adenosine Deaminase-Deficient Severe Combined Immunodeficiency and Diffuse Large B-Cell Lymphoma
TLDR
In patients who lack an HLA-identical bone marrow donor, enzyme replacement therapy with polyethylene glycol-conjugated ADA (PEG-ADA) can correct metabolic abnormalities and permit the recovery of protective immune function. Expand
Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency
TLDR
Clinical therapeutic efficacy from gene therapy for ADA-deficient SCID is demonstrated with an excellent clinical safety profile, and no patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. Expand
Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning
TLDR
Treatment outcomes in two adenosine deaminase (ADA)-deficiency patients who received stem cell gene therapy (SCGT) with no cytoreductive conditioning provide insights into SCGT for ADA deficiency, and reiterate the importance of cytore ductive conditioning to ensure greater benefits from SCGT. Expand
A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient
TLDR
A 24-year course of treatment in a patient who was diagnosed with ADA deficiency has resulted in near-normalization of lymphocyte counts, and this patient is among the longest to be maintained on PEG-ADA enzyme replacement therapy. Expand
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References

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Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications.
TLDR
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. Expand
Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.
TLDR
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. Expand
Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy.
TLDR
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. Expand
Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.
TLDR
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. Expand
Gene Therapy in Peripheral Blood Lymphocytes and Bone Marrow for ADA− Immunodeficient Patients
TLDR
Results indicate successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny. Expand
Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning
TLDR
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. Expand
Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning.
TLDR
It is document successful reconstitution of immune function in a child with the adenosine deaminase (ADA)-deficient form of severe combined immunodeficiency (SCID) following hematopoietic stem cell (HSC) gene therapy. Expand
T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates
TLDR
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. Expand
Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).
TLDR
The lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements, and a gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. Expand
Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.
TLDR
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. Expand
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