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The term gene therapy describes treatment resulting from expression of a transferred gene (or transgene) in diseased or other cells by engineered vectors. Once within the cell, the transgene can direct synthesis of a therapeutic protein that can complement a genetic deficiency or confer upon the cell a desired phenotype or function. Many clinical trials have involved gene therapy for patients with various gene-deficient hematologic diseases, such as severe combined immunodeficiency, hemophilia, Wiskott-Aldrich syndrome, chronic granulomatous disease, aplastic anemia, hemoglobinopathies, HIV infection, and leukemia. Results from some clinical trials indicate that gene therapy can cure or improve many inherited or acquired hematologic disorders. This chapter reviews the basic principles of gene transfer and the results of selected preclinical and clinical studies.

Acronyms and Abbreviations

AAV, adeno-associated virus; ADA-SCID, adenosine deaminase deficiency severe combined immunodeficiency; ARSA, arylsulfatase A; BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea; CAR, chimeric antigen receptor; CCR5, chemokine (C-C motif) receptor 5 gene; CGD, chronic granulomatous disease; CLL, chronic lymphocytic leukemia; CRISPR, clustered, regularly interspaced, short palindromic repeats; DSB, double-stranded break; FA, Fanconi anemia; FVIII, factor VIII; FIX, factor IX; GCV, ganciclovir; GVHD, graft-versus-host disease; Hgb, hemoglobin; HR, homologous recombination; HSC, hematopoietic stem cell; HSV, herpes simplex virus; HSV-TK, herpes simplex virus thymidine kinase; iCasp9, inducible caspase 9 protein; IL2RG, interleukin-2 receptor gene; LTRs, the long terminal repeats; MGMT, O6-methylguanine-DNA methyltransferase; MLD, metachromatic leukodystrophy; SIN, self-inactivating; siRNA, small interfering RNA; TALEN, transcription activator-like effector nuclease; TMZ, temozolomide; WAS, Wiskott-Aldrich syndrome; X-ALD, X-linked adrenoleukodystrophy; X-SCID, X-linked severe combined immunodeficiency; ZFN, zinc-finger nuclease.


Gene therapy is a promising treatment for several inherited or acquired hematologic disorders. Gene therapy involves the introduction of a functional gene to replace a mutated gene or a therapeutic gene to provide a missing or defective protein to the organism. In some cases, the patient’s blood cells are removed and special, targeted cells such as hematopoietic stem cells (HSCs) are selected for engineering. The therapeutic genes are introduced into a vector and delivered into the targeted cells. These targeted, gene-modified cells are reinfused back into the patient. Because this method modifies cells outside the patient’s body, it is called ex vivo gene therapy (Fig. 29–1A). By contrast in vivo gene therapy describes the therapeutic gene-containing vectors being directly injected into the patient (Fig. 29–1B). In the in vivo case, the gene is expressed, producing a therapeutic protein for treatment. Theoretically, if the gene-modified cells are long-lived and able to expand inside the body, a single gene therapy can be sufficient to provide a lifelong therapeutic effect. Current gene therapy technologies have reached the point that many types of single-gene hematologic deficiency diseases can be permanently corrected, for example, X-linked severe combined immunodeficiency (X-SCID) and adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID).

Figure 29–1.

A. Ex vivo gene therapy involves 4 steps: 1. Obtain patient’s blood (HSCs or T cells); ...

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