Journal
BLOOD
Volume 122, Issue 1, Pages 23-36Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-01-306647
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Funding
- Howard Hughes Medical Institute
- National Institutes of Health National Heart, Lung, and Blood Institute [P01 HL64190, P01 HL078810]
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Gene therapy products for the treatment of genetic diseases are currently in clinical trials, and one of these, an adenoassociated viral (AAV) product, has recently been licensed. AAV vectors have achieved positive results in a number of clinical and preclinical settings, including hematologic disorders such as the hemophilias, Gaucher disease, hemochromatosis, and the porphyrias. Because AAV vectors are administered directly to the patient, the likelihood of a host immune response is high, as shown by human studies. Preexisting and/or recall responses to the wild-type virus from which the vector is engineered, or to the transgene product itself, can interfere with therapeutic efficacy if not identified and managed optimally. Small-scale clinical studies have enabled investigators to dissect the immune responses to the AAV vector capsid and to the transgene product, and to develop strategies to manage these responses to achieve long-term expression of the therapeutic gene. However, a comprehensive understanding of the determinants of immunogenicity of AAV vectors, and of potential associated toxicities, is still lacking. Careful immunosurveillance conducted as part of ongoing clinical studies will provide the basis for understanding the intricacies of the immune response in AAV-mediated gene transfer, facilitating safe and effective therapies for genetic diseases.
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