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Published on: November 4, 2018
A new direction for gene therapy: intrathymic T cell-specific lentiviral gene transfer
Ruth Seggewiss1, Cynthia E Dunbar
1National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892, USA.
Abstract:
Reports of neoplasia related to insertional activation of protooncogenes by retroviral vectors have raised serious safety concerns in the field of gene therapy. Modification of current approaches is urgently required to minimize the deleterious consequences of insertional mutagenesis. In this issue of the JCI, Adjali and colleagues report on their treatment of SCID mice lacking the 70-kDa protein tyrosine kinase, ZAP-70, with direct intrathymic injection of a ZAP-70-expressing T cell-specific lentiviral vector, which resulted in T cell reconstitution. Using lentiviral vectors and in situ gene transfer may represent a safer approach than using retroviral vectors for ex vivo gene transfer into HSCs, avoiding 3 factors potentially linked to leukemogenesis, namely HSC targets, ex vivo transduction and expansion, and standard Moloney leukemia virus-based retroviral vectors.
Insights
Gene therapy using lentiviral vectors offers a safer alternative to retroviral vectors for treating severe combined immunodeficiency (SCID). This approach successfully reconstituted T cells in SCID mice, minimizing risks associated with insertional mutagenesis.
Area of Science:
- Gene Therapy
- Immunology
- Virology
Background:
- Insertional activation of protooncogenes by retroviral vectors has raised safety concerns in gene therapy, necessitating safer approaches.
- Severe combined immunodeficiency (SCID) is a group of inherited disorders characterized by profound defects in T cell and B cell immunity.
Discussion:
- This study investigated the use of a T cell-specific lentiviral vector for direct intrathymic gene transfer in SCID mice lacking ZAP-70.
- Lentiviral vectors, when used for in situ gene transfer, may circumvent risks associated with ex vivo gene transfer into hematopoietic stem cells (HSCs) using retroviral vectors.
Key Insights:
- Direct intrathymic injection of a ZAP-70-expressing lentiviral vector led to T cell reconstitution in SCID mice.
- This method avoids HSC targeting, ex vivo transduction, and expansion, which are factors linked to leukemogenesis.
Outlook:
- Lentiviral vectors and in situ gene transfer represent a potentially safer strategy for gene therapy in SCID and other genetic disorders.
- Further research is warranted to fully evaluate the long-term safety and efficacy of this approach in clinical settings.
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