Development of lentiviral gene therapy for Wiskott Aldrich syndrome.

BACKGROUND: Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency. This complex disease is characterised by microthrombocytopenia, recurrent infections, eczema and is associated with a high incidence of autoimmunity and of lymphoid malignancies. WAS is attracting growing attention not only because it highlights the rich cellular and systems biology revolving around cytoskeletal regulation but also because it is candidate for a haematopoietic stem cell gene therapy indication.

OBJECTIVES: As several groups are developing this novel approach, this review discusses the state of the art and challenges in clinical development of gene therapy for WAS, with particular regard to biosafety.

METHODS: In spite of the successes of haematopoietic gene therapy for genetic immune deficiencies, there is a need for more efficient transduction protocols and for vectors with a superior safety profile. Preclinical studies have provided reasonable expectations that haematopoietic gene therapy with a self-inactivated HIV-1-derived vector using the native gene promoter for expression of the WAS transgene will be safe and will lead to the restoration of WAS protein in the haematopoietic and immune system at levels sufficient to provide an improvement in the condition of WAS patients.

CONCLUSIONS: Phase I/II clinical studies will soon be initiated in several European centres to assess the safety and efficacy of this lentiviral vector in WAS patients.