A possible turning point in the hematopoietic stem cell gene therapy for primary immunodeficiency diseases? Lentiviral vectors could take the place of retroviral vectors

Abstract

Evaluation of: Aiuti A, Biasco L, Scaramuzza S et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341(6148), 1233151 (2013).

Wiskott–Aldrich syndrome (WAS), an X-linked primary immunodeficiency disease (PID) with unique and characteristic features, had been considered to be a good candidate for gene therapy. In 2010, hematopoietic stem cell (HSC) gene therapy, using a retroviral vector, was performed for WAS patients; however, concerns remain regarding the long-term safety of this therapy as several patients with PID developed myeloproliferative diseases due to insertional mutagenesis related to HSC gene therapy using retroviral vectors. Aiuti et al. first reported HSC gene therapy for WAS using a lentiviral vector and compared the safety and efficacy of the two therapies in the context of the same disease background. They undertook a detailed study of the vector integration sites and concluded that lentiviral HSC gene therapy was safer than retroviral gene therapy.

Keywords::

• hematopoietic stem cell gene therapy
• lentiviral vector
• retroviral vector
• vector integration sites
• Wiskott–Aldrich syndrome

Financial & competing interests disclosure

The author has received financial support for Research on Intractable Diseases from the Japanese Ministry of Health, Labor and Welfare. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Hematopoietic stem cell (HSC) gene therapy with a third-generation self inactivating (SIN) lentiviral vector containing an endogenous Wiskott-Aldrich syndrome promoter resulted in good clinical efficacy, apart for platelet count normalization, in three WAS patients.

• • Clonal enrichment of the integration sites targeting oncogenes occurred early in the follow-up after retroviral gene therapy, whereas oncogenic integration sites were not overrepresented after lentiviral gene therapy.

• • Lentiviral HSC gene therapy is safer than retroviral HSC gene therapy for WAS, although confirmation of this finding through the long-term observation of larger patient populations is needed.