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The term gene therapy describes treatment resulting from insertion of a gene(s) into somatic cells. High-level expression of a transferred gene (or transgene) can be achieved in almost any type of mammalian cell. Once inside the cell, the transgene can direct synthesis of an intracellular cell surface or secreted protein that can complement a genetic deficiency or confer upon the cell a desired phenotype or function. Alternatively, the transferred genetic material can repress expression of genes encoding unwanted or mutated proteins through “gene interference” or gene complementation. Conceivably, transfer and expression of appropriate genes could correct genetic deficiencies or generate somatic cells with a desired characteristic(s) that can result in therapeutic benefit. Many clinical trials have involved gene therapy for patients with various hematologic diseases, such as leukemia, lymphoma, Gaucher disease, aplastic anemia, hemoglobinopathies, or coagulation factor deficiencies. Results from some clinical trials suggest gene therapy may be useful for treatment of a variety of genetic or acquired diseases, including hematologic disorders. This chapter reviews the basic principles of gene transfer and the results of selected preclinical and clinical studies.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: AAV, adeno-associated virus; ADA, adenosine deaminase; AML, acute myelogenous leukemia; ASCT, autologous stem cell transplant; CAR, coxsackie adenovirus receptor; cDNA, copy or complementary DNA; CLL, chronic lymphocytic leukemia; dsDNA, double-stranded DNA; dsRNA, double-stranded RNA; GM-CSF, granulocyte-monocyte colony-stimulating factor; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; IL-2RG, interleukin-2 receptor gene; NPM-ALK, nucleophosmin-anaplastic lymphoma kinase; OS, overall survival; RFS, relapse-free survival; RNAi, RNA interference; siRNA, small interfering RNA; TNF, tumor necrosis factor.

Virus Vectors

Vectors can be derived from viruses such as retroviruses or adenoviruses. Such vectors can transfer their genetic material into somatic cells with high efficiency. Virus entry can be accomplished by binding to cell surface receptors or through nonspecific attachment. Typically, such viruses bind and enter host cells via receptor-mediated endocytosis, allowing for efficient entry of the virus genetic material into the cell. Table 27–1 lists the cell receptors for specific virus vectors.

Table 27–1. Vectors Used in Gene Therapy and Their Receptors

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