Progress in Genetic Therapy for Severe Combined Immunodeficiency Associated With Adenosine Deaminase Deficiency
Authors: David A Williams
Journal: Molecular Therapy (2009)

A recent report in the New England Journal of Medicine provides details of the long-term follow-up of 10 patients treated with stem cell gene therapy for severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency.1Aiuti A Cattaneo F Galimberti S Benninghoff U Cassani B Callegaro L et al.Gene therapy for immunodeficiency due to adenosine deaminase deficiency.N Engl J Med. 2009; 360: 447-458Crossref PubMed Scopus (826) Google Scholar The results show significant success in reversal of the life-threatening immunodeficiency phenotype and a lack of the insertional mutagenesis that was reported in both the X-linked SCID (X-SCID)2Hacein-Bey-Abina S Le Deist F Carlier F Bouneaud C Hue C De Villartay J-P et al.Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.N Engl J Med. 2002; 346: 1185-1193Crossref PubMed Scopus (996) Google Scholar,3Gaspar HB Parsley KL Howe S King D Gilmour KC Sinclair J et al.Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.Lancet. 2004; 364: 2181-2187Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar and chronic granulomatous disease (CGD)4Ott MG Schmidt M Schwarzwaelder K Stein S Siler U Koehl U et al.Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1.Nat Med. 2006; 12: 401-409Crossref PubMed Scopus (988) Google Scholar trials. Overall, the report shows outcomes in this disease that compare very favorably with current stem cell transplantation and enzyme-replacement therapeutic modalities. Aiuti et al.1Aiuti A Cattaneo F Galimberti S Benninghoff U Cassani B Callegaro L et al.Gene therapy for immunodeficiency due to adenosine deaminase deficiency.N Engl J Med. 2009; 360: 447-458Crossref PubMed Scopus (826) Google Scholar report the use of a γ-retrovirus vector to transduce purified CD34 cells from children with ADA-SCID. Follow-up ranged from 1.8 to 8 years. Gene therapy restored normal immune function in one half of the patients, and in the remaining patients the authors observed significant improvements in some immune function with reduced frequency of infections. No serious adverse events related to vector insertion were reported. Two patients had prolonged neutropenia (one with hypertension and autoimmune thrombocytopenia and one with thrombocytopenia), and one patient developed autoimmune hepatitis. Prolonged neutropenia in both patients appeared related to abnormal busulfan metabolism kinetics. All but two patients remain off chronic pegylated (PEG) ADA therapy. The majority of the patients are now living normal lives and demonstrated enhanced growth, a hallmark of restored immune function and global detoxification of metabolic abnormalities associated with the disease. What have we learned from this successful trial, and what can we extrapolate to other diseases? Several aspects of the study are noteworthy. First, the lack of apparent insertional mutagenesis in the setting of a γ-retrovirus containing an intact long-terminal repeat in this disease along with insertions that appear to lead to clonal expansion in other diseases (LMO2 in X-SCID and MDS/EVI-1 in CGD) provide additional evidence that insertional activation and selection in vivo is a complicated and most likely multifactorial phenomenon. Such integrations may be affected by the availability of specific target cells in particular diseases and strong selective pressures on certain cell types in addition to vector-intrinsic characteristics. In addition, the authors note that (i) the use of nonmyeloablative preparatory chemotherapy (in this case busulfan) and (ii) the withdrawal of enzyme replacement (PEG-ADA) were critical to the success of the experimental therapy. While reconstitution of the lymphoid lineage was significantly higher than myeloid cells, as would be predicted from a selective pressure on the immune system, myeloid reconstitution of transduced cells was robust (~4−9%) compared with previous studies. The authors point to a positive correlation between chemotherapy-induced neutropenia and myeloid cell marking. However, some caution in these interpretations is warranted. The first conclusion (point i, above) is based on the assumption that the ADA-SCID phenotype has no hematopoietic stem cell component; the second (ii) is based on previous, very limited experience with gene therapy in a setting where enzyme-replacement therapy was not disrupted. Although the data presented in this report are clear, more experience needs to be accumulated in other diseases using nonmyeloablative conditioning before the utility of this approach can be widely extrapolated to other diseases. It is likely that the role of cessation of enzyme replacement in ADA-SCID gene therapy will never be rigorously tested. As has been suggested in previous studies, the authors also point out that the number of infused CD34+ cells and the efficiency of gene transfer were also critical for success. Indeed, in the previous X-SCID trials2Hacein-Bey-Abina S Le Deist F Carlier F Bouneaud C Hue C De Villartay J-P et al.Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy.N Engl J Med. 2002; 346: 1185-1193Crossref PubMed Scopus (996) Google Scholar,3Gaspar HB Parsley KL Howe S King D Gilmour KC Sinclair J et al.Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector.Lancet. 2004; 364: 2181-2187Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar and a reported trial in Fanconi anemia,5Kelly PF Radtke S von Kalle C Balcik B Bohn K Mueller R et al.Stem cell collection and gene transfer in Fanconi anemia.Mol Ther. 2007; 15: 211-219Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar infusion of less than ~2 × 106 CD34+ cells/kg has been associated with lack of significant long-term engraftment of genetically modified cells. In all successful trials to date, transduction of greater than ~20% of CD34-derived colony-forming units appears critical. Overall, this report, along with the therapeutic successes in the X-SCID and CGD trials (adverse events notwithstanding), provides solid support for gene transfer technology as a therapeutic modality in diseases of the blood. While longer follow-up and larger numbers of patients are needed to better validate this modality, current trials in other hematopoietic diseases will continue to define the optimal vector systems and appropriate conditioning regimens—both of which will undoubtedly need to be disease-specific for success.