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

Emma C. Morris, Thomas Fox, Ronjon Chakraverty, Rita Tendeiro, Katie Snell, Christine Rivat, Sarah Grace, Kimberly Gilmour, Sarita Workman, Karen Buckland, Katie Butler, Ronnie Chee, Alan D. Salama, Hazem Ibrahim, Havinder Hara, Cecile Duret, Fulvio Mavilio, Frances Male, Frederick D. Bushman, Anne Galy, Siobhan O. Burns, H. Bobby Gaspar and Adrian J. Thrasher

Key points

  • We describe the first successful use of gene therapy in a severely affected adult with Wiskott-Aldrich syndrome.

  • Gene therapy is a viable strategy for adult WAS patients with severe chronic disease complications where allogeneic transplantation presents.


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 harbouring integrations near oncogenes. Here, we describe a case of a pre-splenectomised 30 year old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, 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 pro-inflammatory 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 #NCT01347242.

  • Submitted April 5, 2017.
  • Accepted July 4, 2017.