Evolving Gene Therapy in Primary Immunodeficiency
2017; Elsevier BV; Volume: 25; Issue: 5 Linguagem: Inglês
10.1016/j.ymthe.2017.03.018
ISSN1525-0024
AutoresAdrian J. Thrasher, David A. Williams,
Tópico(s)RNA Interference and Gene Delivery
ResumoPrior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening availability of newborn screening, major improvements in the application of allogeneic procedures, and the emergence of successful hematopoietic stem and progenitor cell (HSC/P) gene therapy, the majority of these children can be identified and cured. Here, we trace key steps in the development of clinical gene therapy for SCID and other primary immunodeficiencies (PIDs), and review the prospects for adoption of new targets and technologies. Prior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening availability of newborn screening, major improvements in the application of allogeneic procedures, and the emergence of successful hematopoietic stem and progenitor cell (HSC/P) gene therapy, the majority of these children can be identified and cured. Here, we trace key steps in the development of clinical gene therapy for SCID and other primary immunodeficiencies (PIDs), and review the prospects for adoption of new targets and technologies. Primary immunodeficiencies (PIDs) are a diverse group of rare, largely monogenic disorders that result in variable susceptibility to infection, autoimmunity/inflammation, and in some cases, malignancy. More than 300 genes have now been associated with syndromic and non-syndromic PID, including the most frequently occurring forms.1Picard C. Al-Herz W. Bousfiha A. Casanova J.L. Chatila T. Conley M.E. Cunningham-Rundles C. Etzioni A. Holland S.M. Klein C. et al.Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.J. Clin. Immunol. 2015; 35: 696-726Crossref PubMed Scopus (117) Google Scholar The severest PIDs present early in life with failure to thrive and severe infections (often opportunistic), and they are usually fatal unless definitive therapy can be implemented rapidly.2Fischer A. Notarangelo L.D. Neven B. Cavazzana M. Puck J.M. Severe combined immunodeficiencies and related disorders.Nat. Rev. Dis. Primers. 2015; 1: 15061Crossref PubMed Google Scholar Fortunately, many of these immunological defects are intrinsic to the hematopoietic system, making them tractable targets for allogeneic hematopoietic stem cell transplantation (HSCT). Since the first successful bone marrow transplants in two PIDs, X-linked severe combined immunodeficiency (SCID) (SCID-X1) and Wiskott-Aldrich syndrome (WAS), HSCT methodologies and technologies (including conditioning regimens) have improved, and the morbidity and mortality associated with this procedure have diminished considerably.3Gatti R.A. Meuwissen H.J. Allen H.D. Hong R. Good R.A. Immunological reconstitution of sex-linked lymphopenic immunological deficiency.Lancet. 1968; 2: 1366-1369Abstract PubMed Google Scholar, 4Bach F.H. Albertini R.J. Joo P. Anderson J.L. Bortin M.M. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome.Lancet. 1968; 2: 1364-1366Abstract PubMed Google Scholar, 5Gennery A.R. Slatter M.A. Grandin L. Taupin P. Cant A.J. Veys P. Amrolia P.J. Gaspar H.B. Davies E.G. 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Some conditions are better candidates than others due to disease-specific characteristics, and risks are heightened in patients who are actively infected or who have developed chronic complications at the time of treatment. More than 30 years ago, the demonstration of retroviral gene transfer to hematopoietic stem and progenitor cells (HSC/Ps) led to the suggestion that this technology could provide an alternative platform for development of therapies in a number of diseases that were amenable to HSCT.7Joyner A. Keller G. Phillips R.A. Bernstein A. Retrovirus transfer of a bacterial gene into mouse haematopoietic progenitor cells.Nature. 1983; 305: 556-558Crossref PubMed Google Scholar, 8Williams D.A. Lemischka I.R. Nathan D.G. Mulligan R.C. Introduction of new genetic material into pluripotent haematopoietic stem cells of the mouse.Nature. 1984; 310: 476-480Crossref PubMed Scopus (263) Google Scholar, 9Dick J.E. Magli M.C. Huszar D. Phillips R.A. Bernstein A. 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For some conditions it was expected that corrected cells would have a profound growth and survival advantage, allowing reconstitution from relatively low numbers of cells. In addition, expression of transgenes at supraphysiological levels was anticipated to allow "cross-correction" of other deficient non-hematopoietic cells in some diseases.12Williams D.A. Broadening the indications for hematopoietic stem cell genetic therapies.Cell Stem Cell. 2013; 13: 263-264Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Over a number of years, successful correction of cellular and animal models boosted expectation that gene therapy would rapidly become mainstream, but clinical translation proved more difficult (Figure 1). 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Immunological reconstitution has in general been robust, with high-level gene marking in lymphocytes and, for the first time, albeit at lower levels in myeloid cells, which is an effective surrogate for HSC/P marking in bone marrow. Permanent withdrawal of immunoglobulin supplementation was achieved in approximately 50% of patients, suggesting that further improvements are still possible. Recently, a collaboration among GlaxoSmithKline (GSK), Fondazione Telethon, and Ospedale San Raffaele secured European Marketing Authorisation for Strimvelis TM, which is the original LTR-based vector studied in Milan.22Bordignon C. Notarangelo L.D. Nobili N. Ferrari G. Casorati G. Panina P. Mazzolari E. Maggioni D. Rossi C. Servida P. et al.Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients.Science. 1995; 270: 470-475Crossref PubMed Google Scholar From proof of concept in humans to this first ex vivo market authorization for a gene therapy product, vector technology has advanced considerably. HIV-1-based lentiviruses in particular have been adopted as the current vector of choice for HSC/P gene transfer because they appear to offer some advantages in terms of mutagenicity (because of a more favorable genome insertion profile within transcriptional units rather than at transcription start sites [TSSs], a theoretical advantage), lack of intrinsic retroviral LTR enhancer activity (a modification that has also been duplicated in a new generation of gammaretroviruses), and higher efficiency of gene transfer.33Naldini L. Blömer U. Gallay P. Ory D. Mulligan R. Gage F.H. Verma I.M. Trono D. 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Ther. 2017; 6: 1-14Google Scholar However, this still does not explain the lack of myeloid toxicity unless a similar argument can be applied to the bone marrow microenvironment or even during ex vivo culture. X-linked SCID (for SCID-X1) is the most common form of SCID, accounting for 40%–50% of all cases.2Fischer A. Notarangelo L.D. Neven B. Cavazzana M. Puck J.M. Severe combined immunodeficiencies and related disorders.Nat. Rev. Dis. Primers. 2015; 1: 15061Crossref PubMed Google Scholar Mutations in the IL2RG gene lead to defective expression of the common cytokine receptor gamma chain (gc), so-called because it is a subunit shared by multiple cytokine receptors, including the interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor complexes, which are variably involved in the development and function of all lymphocytes. As a consequence, patients show profound defects of adaptive immunity, resulting from the low number or absence of T and natural killer (NK) lymphocytes, and the loss of function of B lymphocytes. The first two clinical trials of gene therapy for SCID-X1 included a total number of 20 subjects and were conducted using virtually identical LTR-intact gammaretroviral vectors and very similar transduction protocols.42Cavazzana-Calvo M. Hacein-Bey S. de Saint Basile G. Gross F. Yvon E. Nusbaum P. Selz F. Hue C. Certain S. Casanova J.L. et al.Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease.Science. 2000; 288: 669-672Crossref PubMed Scopus (1861) Google Scholar, 43Gaspar H.B. Parsley K.L. Howe S. King D. Gilmour K.C. Sinclair J. Brouns G. Schmidt M. Von Kalle C. 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Med. 2012; 209: 1409-1417Crossref PubMed Scopus (45) Google Scholar If this is the case, then use of conditioning would likely reduce risk for clinically manifesting mutagenesis. No convincing evidence could be confirmed for a pathogenic role of non-physiological expression of the transgene in leukemogenesis through aberrant receptor signaling, although, of course, it allowed the T cell maturation to proceed.53Scobie L. Hector R.D. Grant L. Bell M. Nielsen A.A. Meikle S. Philbey A. Thrasher A.J. Cameron E.R. Blyth K. Neil J.C. A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity.Mol. Ther. 2009; 17: 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar All patients were treated with relatively standard chemotherapy, but one patient died of refractory leukemia. Remarkably, the four surviving patients recovered their T cell immunity after completion of chemotherapy without need for any further intervention. This suggests that very long-lasting (possibly self-renewing), gene-corrected T cell precursors engrafted in the thymus soon after infusion of cells, and that these are capable of sustaining active thymopoiesis for many years. Molecular studies in mice engrafted with cells transduced with replication-incompetent gammaretroviral vectors identified duplicated enhancer elements in the LTR as the major culprit driving dysregulated gene expression in the neighborhood of the RIS.37Li Z. Düllmann J. Schiedlmeier B. Schmidt M. von Kalle C. Meyer J. Forster M. Stocking C. Wahlers A. Frank O. et al.Murine leukemia induced by retroviral gene marking.Science. 2002; 296: 497Crossref PubMed Scopus (514) Google Scholar, 54Modlich U. Bohne J. Schmidt M. von Kalle C. Knöss S. Schambach A. Baum C. Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity.Blood. 2006; 108: 2545-2553Crossref PubMed Scopus (208) Google Scholar, 55Kustikova O. Fehse B. Modlich U. Yang M. Düllmann J. Kamino K. von Neuhoff N. Schlegelberger B. Li Z. Baum C. Clonal dominance of hematopoietic stem cells triggered by retroviral gene marking.Science. 2005; 308: 1171-1174Crossref PubMed Scopus (269) Google Scholar This effect was also shown to have activity over quite long ranges and to operate in combination with other molecular lesions.50Howe S.J. Mansour M.R. Schwarzwaelder K. Bartholomae C. Hubank M. Kempski H. Brugman M.H. Pike-Overzet K. Chatters S.J. de Ridder D. et al.Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients.J. Clin. Invest. 2008; 118: 3143-3150Crossref PubMed Scopus (615) Google Scholar, 51Hacein-Bey-Abina S. Garrigue A. Wang G.P. Soulier J. Lim A. Morillon E. 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