Editors' ChoiceGene Therapy

Gene therapy hide and seek

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Science Translational Medicine  21 Oct 2015:
Vol. 7, Issue 310, pp. 310ec178
DOI: 10.1126/scitranslmed.aad4447

Gene therapy leverages the infectivity of viruses to deliver therapeutic genes to cells in need of them. Adeno-associated viruses (AAVs), which are not known to cause human disease but infect both quiescent and dividing cells with minimal genome integration, are frequently used as vectors for gene therapy delivery. However, AAVs induce immune responses, limiting their use in preexposed individuals. There is a growing demand for a variety of AAV vehicles tailored to deliver genes to different target organs as well as those that bypass preexisting immunity. Now, Hui et al. identify common epitopes between various types of AAVs that lead to immune cell recognition.

Immunological studies of AAV vectors in humans have been limited by sample size in peripheral blood, the most commonly available source from clinical trials. The authors overcame this limitation using spleen cells isolated from patients who have undergone splenectomy for nonmalignant indications. The spleen lymphocytes from patients were expanded and used as canaries in a coal mine, reacting to a variety of AAV epitopes. The information obtained by using human spleen lymphocytes is particularly useful, as there is no reliable animal model of human T cell responses against the AAV capsid. Precise mapping of common capsid epitopes was made possible thanks to this system. Thus far, AAV vehicles have only been optimized for their gene delivery efficacy. These findings may make it possible to design AAVs that can avoid a cellular immune response.

D. J. Hui et al., AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes. Mol. Ther. Methods Clin. Dev. 10.1038/mtm.2015.29 (2015). [Full Text]

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