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In the past 5 years, gene therapy as a promise for hematologic diseases has become a reality. In fact, the term has expanded from providing genetic material to treat disease to incorporating a normal gene or cDNA to replace a defective or nonfunctional gene, or CRISPR (clustered regularly interspaced short palindromic repeats) genetic engineering to correct a point mutation. This has been a revolutionary period in a field first imagined in the 1980s. Treatment resulting from expression of a transferred gene (or transgene) in diseased or other cells by engineered vectors has now become approved by the U.S. Food and Drug Administration (FDA), and many other treatments are in development. When within the cell, and most often incorporated into DNA, 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 or genetically mutational hematologic diseases, such as severe combined immunodeficiency, hemophilia, sickle cell disease, thalassemia, Wiskott-Aldrich syndrome, chronic granulomatous disease, congenital neutropenia, and HIV infection. Early results from these clinical trials indicate that gene therapy can cure or improve many inherited or acquired hematologic disorders. Recently, initial FDA and European approvals have been forthcoming. 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; ABCD1, adenosine triphosphate binding cassette transporter; ADA-SCID, deaminase deficiency severe combined immunodeficiency; AIDS, the acquired immunodeficiency syndrome; ARSA, arylsulfatase A; BCL11A, B-cell lymphoma/leukemia 11A; BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea; CAR, chimeric antigen receptors; CCR5: chemokine (C-C motif) receptor 5 gene; CGD, chronic granulomatous disease; CLL, chronic lymphocytic leukemia; CRISPR, clustered, regularly interspaced, short palindromic repeats; DELTA-1, Drosophila Delta homolog-1; dsDNA, double-stranded DNA; FA, Fanconi anemia; GM-CSF, granulocyte-monocyte colony-stimulating factor; FVIII, factor VIII of coagulation pathway; FVIX, factor IX of coagulation pathway; GvHD, Graft vs. Host Disease; HMGA2 , High-mobility group AT-hook 2; HIV, human immunodeficiency virus; HOXB4 , Homeobox protein B4; HSC, hematopoietic stem cells; HSV, herpes simplex virus; HSV-TK, herpes simplex virus thymidine kinase; iCasp9, inducible caspase 9 protein; ICER, the incremental cost-effectiveness ratios; IL-2RG, interleukin-2 receptor gene; kbps, kilobase pairs; LMO2, LIM domain only 2 (rhombotin-like 1);LTRs, the long terminal repeats; LT-HSC, long term hematopoietic stem cells; MGMT, O6-methylguanine-DNA methyltransferase; MLD, metachromatic leukodystrophy; MGMT, O6-methylguanine-DNA methyltransferase; (QALY, quality-adjusted life-year; SCID, severe combined immunodeficiency; sh, a short hairpin; RNA siRNA, small interfering RNA; TALEN, transcription activator- like effector nuclease; TCR, T-cell receptor; TMZ, temozolomide; WAS, Wiskott-Aldrich syndrome; WASp, WAS protein, X-ALD, X- linked adrenoleukodystrophy; X-SCID, X-linked severe combined immunodeficiency; ZFN, zinc-finger nuclease.


Gene therapy is a promising treatment for many inherited and 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. ...

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