Gene therapy for PNP deficiency protocol
Abstract
Purine nucleoside phosphorylase (PNP) is a key enzyme required for the degradation of purine nucleosides into uric acid or their salvage into nucleic acids. Patients who are deficient in PNP suffer from progressive T cell immunodeficiency, with increased susceptibility to infections, autoimmunity, and neurologic abnormalities. In the absence of successful treatment to restore immune function, these patients rarely survive to adulthood. Hematopoietic stem cell transplantation is the only known cure for PNP deficiency. Use of an HLA-matched donor is preferable as the outcome with alternative donors have been variable; however, this option is rarely available.
Gene therapy represents a therapeutic option that bypasses the need for a donor, and thus associated complications. Although first generation γ-retroviral vectors have been successful in some immunodeficiencies, in others, evidence of insertional mutagenesis prompted a halt in their use. More recently, the introduction of safer lentiviral vectors holds promise in offering a viable option to treat immunodeficiency.
Here, we present a clinical trial protocol utilizing self-inactivating lentiviral vectors to treat PNP deficiency. Patients will be evaluated up to 3 years post-transplantation to determine the safety of lentiviral-treated stem cell infusion, as well as the extent of immune reconstitution.
Statement of novelty: This protocol describes the novel treatment of PNP deficiency using lentiviral-based gene therapy.
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REFERENCES
Aiuti A., Slavin S., Aker M., Ficara F., Deola S., Mortellaro A., Morecki S., Andolfi G., Tabucchi A., Carlucci F., Marinello E., Cattaneo F., Vai S., Servida P., Miniero R., Roncarolo M.G., and Bordignon C. 2002. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science, 296(5577):2410–2413.
Beatty P.G., Clift R.A., Mickelson E.M., Nisperos B.B., Flournoy N., Martin P.J., Sanders J.E., Stewart P., Buckner C.D., Storb R., Thomas E.D., and Hansen J.A. 1985. Marrow transplantation from related donors other than HLA-identical siblings. N. Engl. J. Med. 313(13):765–771.
Brodszki N., Svensson M., van Kuilenburg A.B., Meijer J., Zoetekouw L., Truedsson L., and Toporski J. 2015. Novel genetic mutations in the first Swedish patient with purine nucleoside phosphorylase deficiency and clinical outcome after hematopoietic stem cell transplantation with HLA-matched unrelated donor. JIMD Rep. 24:83–89.
Buckley R.H. 2012. The long quest for neonatal screening for severe combined immunodeficiency. J. Allergy Clin. Immunol. 129(3):597–604.
Caillat-Zucman S., Le Deist F., Haddad E., Gannagé M., Dal Cortivo L., Jabado N., Hacein-Bey-Abina S., Blanche S., Casanova J.L., Fischer A., and Cavazzana-Calvo M. 2004. Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors. Bone Marrow Transplant. 33(11):1089–1095.
Candotti F., Shaw K.L., Muul L., Carbonaro D., Sokolic R., Choi C., Schurman S.H., Garabedian E., Kesserwan C., Jagadeesh G.J., Fu P.Y., Gschweng E., Cooper A., Tisdale J.F., Weinberg K.I., Crooks G.M., Kapoor N., Shah A., Abdel-Azim H., Yu X.J., Smogorzewska M., Wayne A.S., Rosenblatt H.M., Davis C.M., Hanson C., Rishi R.G., Wang X., Gjertson D., Yang O.O., Balamurugan A., Bauer G., Ireland J.A., Engel B.C., Podsakoff G.M., Hershfield M.S., Blaese R.M., Parkman R., and Kohn D.B. 2012. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood, 120(18):3635–3646.
Dalal I., Reid B., Doyle J., Freedman M., Calderwood S., Saunders F., and Roifman C.M. 2000. Matched unrelated bone marrow transplantation for combined immunodeficiency. Bone Marrow Transplant. 25(6):613–621.
Delicou S., Kitra-Roussou V., Peristeri J., Goussetis E., Vessalas G., Rigatou E., Psychou F., Salavoura K., and Grafakos S. 2007. Successful HLA-identical hematopoietic stem cell transplantation in a patient with purine nucleoside phosphorylase deficiency. Pediatr. Transplant. 11(7):799–803.
Douek D.C., McFarland R.D., Keiser P.H., Gage E.A., Massey J.M., Haynes B.F., Polis M.A., Haase A.T., Feinberg M.B., Sullivan J.L., Jamieson B.D., Zack J.A., Picker L.J., and Koup R.A. 1998. Changes in thymic function with age and during the treatment of HIV infection. Nature, 396(690):690–695.
Fischer A., Hacein-Bey-Abina S., and Cavazzana-Calvo M. 2013. Gene therapy of primary T cell immunodeficiencies. Gene, 525(2):170–173.
Gaspar H.B., Bjorkegren E., Parsley K., Gilmour K.C., King D., Sinclair J., Zhang F., Giannakopoulos A., Adams S., Fairbanks L.D., Gaspar J., Henderson L., Xu-Bayford J.H., Davies E.G., Veys P.A., Kinnon C., and Thrasher A.J. 2006. Successful reconstitution of immunity in ADA-SCID by stem cell gene therapy following cessation of PEG-ADA and use of mild preconditioning. Mol. Ther. 14(4):505–513.
George, D.L., and Francke, U. 1976. Gene dose effect: regional mapping of human nuceloside phosphorylase on chromosome 14. Science, 194(4267):851–852. [Online]. Available from http://www.ncbi.nlm.nih.gov/pubmed/824731 [7 June 2018].
Grunebaum E., Cohen A., and Roifman C.M. 2013. Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies. Curr. Opin. Allergy Clin. Immunol. 13(6):630–638.
Grunebaum E., Mazzolari E., Porta F., Dallera D., Atkinson A., Reid B., Notarangelo L.D., and Roifman C.M. 2006. Bone marrow transplantation for severe combined immune deficiency. JAMA, 295(5):508.
Hacein-Bey-Abina S., Garrigue A., Wang G.P., Soulier J., Lim A., Morillon E., Clappier E., Caccavelli L., Delabesse E., Beldjord K., Asnafi V., MacIntyre E., Dal Cortivo L., Radford I., Brousse N., Sigaux F., Moshous D., Hauer J., Borkhardt A., Belohradsky B.H., Wintergerst U., Velez M.C., Leiva L., Sorensen R., Wulffraat N., Blanche S., Bushman F.D., Fischer A., and Cavazzana-Calvo M. 2008. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118(9):3132–3142.
Haddad, E., Landais, P., Friedrich, W., Gerritsen, B., Cavazzana-Calvo, M., Morgan, G., Bertrand, Y., Fasth, A., Porta, F., Cant, A., Espanol, T., Müller, S., Veys, P., Vossen, J., and Fischer, A. 1998. Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients. Blood, 91(10):3646–3653. [Online]. Available from http://www.ncbi.nlm.nih.gov/pubmed/9573000 [8 June 2018].
Hassan A., Booth C., Brightwell A., Allwood Z., Veys P., Rao K., Hönig M., Friedrich W., Gennery A., Slatter M., Bredius R., Finocchi A., Cancrini C., Aiuti A., Porta F., Lanfranchi A., Ridella M., Steward C., Filipovich A., Marsh R., Bordon V., Al-Muhsen S., Al-Mousa H., Alsum Z., Al-Dhekri H., Al Ghonaium A., Speckmann C., Fischer A., Mahlaoui N., Nichols K.E., Grunebaum E., Al Zahrani D., Roifman C.M., Boelens J., Davies E.G., Cavazzana-Calvo M., Notarangelo L., Gaspar H.B., and Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and European Society for Immunodeficiency. 2012. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood, 120(17):3615–3624.
Howe 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., Gilmour K.C., Adams S., Thornhill S.I., Parsley K.L., Staal F.J., Gale R.E., Linch D.C., Bayford J., Brown L., Quaye M., Kinnon C., Ancliff P., Webb D.K., Schmidt M., von Kalle C., Gaspar H.B., and Thrasher A.J. 2008. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J. Clin. Invest. 118(9):3143–3150.
Liao P., Toro A., Min W., Lee S., Roifman C.M., and Grunebaum E. 2008. Lentivirus gene therapy for purine nucleoside phosphorylase deficiency. J. Gene Med. 10(12):1282–1293.
Markert, M.L. 1991. Purine nucleoside phosphorylase deficiency. Immunodefic. Rev. 3(1):45–81. [Online]. Available from http://www.ncbi.nlm.nih.gov/pubmed/1931007 [8 June 2018].
McWilliams L.M., Dell Railey M., and Buckley R.H. 2015. Positive family history, infection, low absolute lymphocyte count (ALC), and absent thymic shadow: diagnostic clues for all molecular forms of severe combined immunodeficiency (SCID). J. Allergy Clin. immunol. Pract. 3(4):585–591.
Mitchell, B.S., Mejias, E., Daddona, P.E., and Kelley, W.N. 1978. Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells. Proc. Natl. Acad. Sci. U. S. A. 75(10):5011–5014. [Online]. Available from http://www.ncbi.nlm.nih.gov/pubmed/311004 [8 June 2018].
Pai S.-Y., Logan B.R., Griffith L.M., Buckley R.H., Parrott R.E., Dvorak C.C., Kapoor N., Hanson I.C., Filipovich A.H., Jyonouchi S., Sullivan K.E., Small T.N., Burroughs L., Skoda-Smith S., Haight A.E., Grizzle A., Pulsipher M.A., Chan K.W., Fuleihan R.L., Haddad E., Loechelt B., Aquino V.M., Gillio A., Davis J., Knutsen A., Smith A.R., Moore T.B., Schroeder M.L., Goldman F.D., Connelly J.A., Porteus M.H., Xiang Q., Shearer W.T., Fleisher T.A., Kohn D.B., Puck J.M., Notarangelo L.D., Cowan M.J., and O’Reilly R.J. 2014. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N. Engl. J. Med. 371(5):434–446.
Roifman C. M., Somech R., Kavadas F., Pires L., Nahum A., Dalal I., and Grunebaum E. 2012. Defining combined immunodeficiency. J. Allergy Clin. Immunol. 130(1):177–183.
Shearer W.T., Dunn E., Notarangelo L.D., Dvorak C.C., Puck J.M., Logan B.R., Griffith L.M., Kohn D.B., O’Reilly R.J., Fleisher T.A., Pai S.Y., Martinez C.A., Buckley R.H., and Cowan M.J. 2014. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J. Allergy Clin. Immunol. 133(4):1092–1098.
Ullman, B., Gudas, L.J., Clift, S.M., and Martin, D.W., Jr. 1979. Isolation and characterization of purine-nucleoside phosphorylase-deficient T-lymphoma cells and secondary mutants with altered ribonucleotide reductase: genetic model for immunodeficiency disease. Proc. Natl. Acad. Sci. U. S. A. 76(3):1074–1078. [Online]. Available from http://www.ncbi.nlm.nih.gov/pubmed/108675 [8 June 2018].
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LymphoSign Journal
Volume 5 • Number 3 • September 2018
Pages: 115 - 120
History
Received: 15 June 2018
Accepted: 9 August 2018
Accepted manuscript online: 17 August 2018
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© 2018.
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LindaVong. 2018. Gene therapy for PNP deficiency protocol. LymphoSign Journal.
5(3): 115-120. https://doi.org/10.14785/lymphosign-2018-0007
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