Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proin-flammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult / Morris, E. C.; Fox, T.; Chakraverty, R.; Tendeiro, R.; Snell, K.; Rivat, C.; Grace, S.; Gilmour, K.; Workman, S.; Buckland, K.; Butler, K.; Chee, R.; Salama, A. D.; Ibrahim, H.; Hara, H.; Duret, C.; Mavilio, F.; Male, F.; Bushman, F. D.; Galy, A.; Burns, S. O.; Gaspar, H. B.; Thrasher, A. J.. - In: BLOOD. - ISSN 0006-4971. - 130:11(2017), pp. 1327-1335. [10.1182/blood-2017-04-777136]

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult

Mavilio F.;
2017

Abstract

Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proin-flammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.
2017
17-lug-2017
130
11
1327
1335
Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult / Morris, E. C.; Fox, T.; Chakraverty, R.; Tendeiro, R.; Snell, K.; Rivat, C.; Grace, S.; Gilmour, K.; Workman, S.; Buckland, K.; Butler, K.; Chee, R.; Salama, A. D.; Ibrahim, H.; Hara, H.; Duret, C.; Mavilio, F.; Male, F.; Bushman, F. D.; Galy, A.; Burns, S. O.; Gaspar, H. B.; Thrasher, A. J.. - In: BLOOD. - ISSN 0006-4971. - 130:11(2017), pp. 1327-1335. [10.1182/blood-2017-04-777136]
Morris, E. C.; Fox, T.; Chakraverty, R.; Tendeiro, R.; Snell, K.; Rivat, C.; Grace, S.; Gilmour, K.; Workman, S.; Buckland, K.; Butler, K.; Chee, R.; ...espandi
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