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Bone marrow gene therapy for adenosine deaminase deficiency
L C Kaptein1, M P Einerhand, E Braakman
1Department of Gene Therapy, Institute of Applied Radiobiology and Immunology, TNO, Rijswijk, The Netherlands.
Immunodeficiency
|January 1, 1993
Summary
Gene therapy offers a promising treatment for adenosine deaminase deficiency (ADA-SCID). Introducing the ADA gene into a patient's own bone marrow cells can restore immune function and correct the deficiency.
Area of Science:
- Immunology
- Molecular Biology
- Gene Therapy
Background:
- Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency disease (SCID).
- Toxic accumulation of 2'-deoxyadenosine particularly affects T cells in ADA-SCID patients.
- Current treatments include bone marrow transplantation, which requires a suitable donor.
Purpose of the Study:
- To develop a gene therapy approach for ADA-SCID using a retroviral vector.
- To restore functional ADA activity in patient-derived cells.
- To assess the long-term efficacy and safety of ADA gene transfer in preclinical models.
Main Methods:
- Generation of a retroviral vector carrying the human ADA gene.
- Transduction of ADA-SCID T cells to restore ADA activity.
- Infection of pluripotent hematopoietic stem cells in murine and non-human primate models.
- Long-term monitoring of human ADA expression in hematopoietic cells post-transplantation.
Main Results:
- Restored normal ADA activity and 2'-deoxyadenosine sensitivity in ADA-SCID T cells.
- Demonstrated long-term (> 6 months) expression of human ADA in the hematopoietic system of mice.
- Confirmed sustained proviral detection in peripheral blood and granulocytes of rhesus monkeys for over a year.
Conclusions:
- Retroviral gene transfer is effective in restoring ADA activity in ADA-SCID cells.
- The developed gene therapy approach shows potential for long-term correction of ADA-SCID.
- A clinical protocol for bone marrow gene therapy in ADA-SCID patients is proposed based on these findings.