Gene therapy for Wiskott-Aldrich syndrome: here to stay
Authors: Fabio Candotti
Journal: The Lancet Haematology (2019)

In The Lancet Haematology, Francesca Ferrua and colleagues1Ferrua F Cicalese MP Galimberti S et al.Lentiviral haemopoietic stem cell or progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study.Lancet Haematol. 2019; (published online April 10.)http://dx.doi.org/10.1016/S2352-3026(19)30021-3Summary Full Text Full Text PDF PubMed Scopus (114) Google Scholar discuss results of an interim analysis of eight patients with Wiskott-Aldrich syndrome who were treated in a phase 1/2 clinical study with lentiviral-mediated gene therapy. The interim analysis was planned for when the first six patients treated had completed at least 3 years of follow-up (median follow-up was 3·6 years [range 0·5–5·6]). The authors reported long-lasting multilineage engraftment of transduced Wiskott-Aldrich syndrome protein (WASP)-expressing cells; restoration of responses to T-cell receptor crosslinking; and substantial clinical improvement, including diminished severity of eczema, reduced frequency and severity of bleeding episodes, and lower incidence of infection episodes. Altogether, the procedure resulted in improved quality of life for treated patients in the face of an acceptable and transitory toxicity burden, restricted to a 6-month period after administration of a reduced-intensity conditioning regimen with busulfan and fludarabine. These findings confirm and expand on previously published work in the initial cohort of patients2Aiuti A Biasco L Scaramuzza S et al.Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.Science. 2013; 341: 1233151Crossref PubMed Scopus (809) Google Scholar, 3Castiello MC Scaramuzza S Pala F et al.B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome.J Allergy Clin Immunol. 2015; 136: 692-702Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar and add to experience reported by other investigators who have used a similar approach to treat the same disease.4Braun CJ Boztug K Paruzynski A et al.Gene therapy for Wiskott-Aldrich syndrome: long-term efficacy and genotoxicity.Sci Transl Med. 2014; 6: 227ra33Crossref PubMed Scopus (364) Google Scholar, 5Hacein-Bey Abina S Gaspar HB Blondeau J et al.Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.JAMA. 2015; 313: 1550-1563Crossref PubMed Scopus (269) Google Scholar, 6Chu JI Henderson LA Armant M et al.Gene therapy using a self-inactivating lentiviral vector improves clinical and laboratory manifestations of Wiskott-Aldrich syndrome.Blood. 2015; 126: 260Google Scholar These results are in line with successes obtained by application of gene therapy to other severe immunodeficiencies;7Cavazzana M Bushman FD Miccio A André-Schmutz I Six E Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges.Nat Rev Drug Discov. 2019; (published online March 11.)DOI:10.1038/s41573-019-0020-9Crossref PubMed Scopus (99) Google Scholar however, Wiskott-Aldrich syndrome poses unique challenges that seem to remain—at least partly—unmet. Compared with other primary immunodeficiencies, the presence of thrombocytopenia is a typical clinical feature of Wiskott-Aldrich syndrome8Candotti F Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome.J Clin Immunol. 2018; 38: 13-27Crossref PubMed Scopus (104) Google Scholar that current gene-transfer therapies have not been able to fully correct. Ferrua and colleagues noted that platelet counts remained below the limits of normal in most treated patients despite increasing from pretreatment values, a finding also described in previous reports.2Aiuti A Biasco L Scaramuzza S et al.Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.Science. 2013; 341: 1233151Crossref PubMed Scopus (809) Google Scholar, 3Castiello MC Scaramuzza S Pala F et al.B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome.J Allergy Clin Immunol. 2015; 136: 692-702Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 5Hacein-Bey Abina S Gaspar HB Blondeau J et al.Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.JAMA. 2015; 313: 1550-1563Crossref PubMed Scopus (269) Google Scholar The reasons why it is difficult to return platelet counts to normal with gene therapy are unclear, but it is possible that—by comparison with lymphoid lineages—WASP expression in platelets and platelet precursors does not result in selective advantage. The relation noted by Ferrua and colleagues between median platelet count and proportion of transduced clonogenic progenitors in bone marrow after gene therapy lends some support to this possibility and suggests that efforts to increase engraftment of WAS gene-corrected progenitors can be pursued as a strategy to improve the effects of the procedure on platelet counts. It is noteworthy that the patients described by Ferrua and colleagues had few or no bleeding complications after gene therapy. If such improvements prove long lasting, they could support the extension of gene therapy to milder forms of Wiskott-Aldrich syndrome that are characterised only by thrombocytopenia and that are presently excluded from enrolment into this clinical trial because of a perceived unfavourable risk:benefit ratio. In addition to strengthening evidence of prospective benefit, the current results show the gene therapy procedure is low risk because no evidence was seen of insertional oncogenesis nor clonal expansion during follow-up. However, because leukaemia complications have occurred beyond 5 years after treatment in other investigations,4Braun CJ Boztug K Paruzynski A et al.Gene therapy for Wiskott-Aldrich syndrome: long-term efficacy and genotoxicity.Sci Transl Med. 2014; 6: 227ra33Crossref PubMed Scopus (364) Google Scholar longer observation periods seem to be warranted to confirm the long-term safety of the procedure. With the increasing availability of gene therapy, the conundrum of whether to choose this newer therapeutic option over the more established treatment of haemopoietic stem/progenitor cell (HSPC) transplantation is facing patients and families. The limited toxicity and absence of mortality among patients with Wiskott-Aldrich syndrome treated with gene therapy contrast with the potential for acute morbidity, long-term complications, and mortality of patients treated with HSPC transplantation, even when reduced intensity conditioning regimens are used that have increased overall survival of treated patients to 90–100%.9Albert MH Slatter M Gennery A et al.Busulfan/fludarabine- or treosulfan/fludarabine-based conditioning regimen in patients with Wiskott-Aldrich syndrome given allogeneic hematopoietic cell transplantation: an EBMT Inborn Errors Working Party and Scetide Retrospective Analysis.Blood. 2018; 132: 2175Google Scholar, 10Elfeky RA Furtado-Silva JM Chiesa R et al.One hundred percent survival after transplantation of 34 patients with Wiskott-Aldrich syndrome over 20 years.J Allergy Clin Immunol. 2018; 142: 1654-1656Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar Risk-averse parents and patients will probably find the gene therapy option more attractive than HSPC transplantation. However, experience of gene therapy is limited to date, with only 15 published clinical cases,1Ferrua F Cicalese MP Galimberti S et al.Lentiviral haemopoietic stem cell or progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study.Lancet Haematol. 2019; (published online April 10.)http://dx.doi.org/10.1016/S2352-3026(19)30021-3Summary Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 5Hacein-Bey Abina S Gaspar HB Blondeau J et al.Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.JAMA. 2015; 313: 1550-1563Crossref PubMed Scopus (269) Google Scholar whereas data for HSPC transplantation derive from observations in hundreds of treated patients with Wiskott-Aldrich syndrome, which might induce a higher level of confidence in this treatment modality. The accumulation of data from larger cohorts of patients with Wiskott-Aldrich syndrome treated with gene therapy and monitored for longer periods is undoubtedly necessary to provide additional points of reference that, perhaps, will help indicate the relative roles of gene therapy and HSPC transplantation in treatment paradigms for Wiskott-Aldrich syndrome. Over the past 10 years, gene therapy for Wiskott-Aldrich syndrome has been revitalised after a series of serious adverse events caused by use of γ-retroviral vectors.8Candotti F Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome.J Clin Immunol. 2018; 38: 13-27Crossref PubMed Scopus (104) Google Scholar As currently practiced using lentiviral vectors, gene therapy for Wiskott-Aldrich syndrome has proven effective at improving all the clinical aspects of the disease while maintaining a favourable safety profile. With the expected continued increase in availability of this therapeutic approach, gene therapy is likely to become an option that is routinely considered for clinical management of patients with Wiskott-Aldrich syndrome. I declare no competing interests. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical studyData from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. Full-Text PDF Open Access