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

  title={Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency},
  author={Francesca Ferrua and Immacolata Brigida and Alessandro Aiuti},
  journal={Current Opinion in Allergy and Clinical Immunology},
Purpose of reviewThe present review describes the recent progress in the treatment of adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) using autologous gene-modified hematopoietic stem cells, comparing immune reconstitution with respect to allogeneic transplant and discussing differences with gene therapy for SCID-X1. Recent findingsSince 2000, more than 30 ADA-SCID patients have been treated with gene therapy worldwide, with successful outcome in most cases, consisting… 

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution.

Gene therapy for primary adaptive immune deficiencies.

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy.

After HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells, suggesting ADA plays an essential role in controlling autore active B cell counterselection by regulating BCR and TLR functions.

Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency

The value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms and the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency are assessed.

B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients.

Adenosine Deaminase Deficiency – More Than Just an Immunodeficiency

This review will outline the impact of ADA deficiency on various organ systems, starting with the well-understood immunological abnormalities and suggest that it should be recognized as a systemic metabolic disorder that affects multiple organ systems.

Hematopoietic stem cell expansion and gene therapy.

Some of the current limitations of HSC gene therapy could be overcome by combining novel HSC expansion strategies with gene therapy, as well as the opportunities presented by implementing ex vivo expansion of gene-modified HSC.



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.

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.

New insights into the pathogenesis of adenosine deaminase-severe combined immunodeficiency and progress in gene therapy

Gene therapy for ADA-deficient SCID is an effective treatment, providing long-term clinical benefit for affected patients, underlining that gene therapy has a favorable safety profile and is effective in restoring normal purine metabolism and immune functions.

How I treat ADA deficiency.

The choice between ERT, MUD transplant, or GT is difficult and dependent on several factors, including accessibility to the different modalities, response of patients to long-term ERTs, and the attitudes of physicians and parents to the short- and potential long- term risks associated with different treatments.

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.

Bone marrow transplantation and alternatives for adenosine deaminase deficiency.

  • H. Gaspar
  • Medicine
    Immunology and allergy clinics of North America
  • 2010

Efficacy of gene therapy for X-linked severe combined immunodeficiency.

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.

Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy.

Gene transfer into HSCs is an effective treatment for SCID, although potentially limited by the risk of insertional mutagenesis, andGene-dense regions, promoters, and transcriptionally active genes were preferred retroviral integrations sites (RISs) both in preinfusion transduced CD34(+) cells and in vivo after gene therapy.