Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID

Laura Garcia-Perez; Marja van Eggermond; Lieke van Roon; Sandra A Vloemans; Martijn Cordes; Axel Schambach; Michael Rothe; Dagmar Berghuis; Chantal Lagresle-Peyrou; Marina Cavazzana; Fang Zhang; Adrian J Thrasher; Daniela Salvatori; Pauline Meij; Anna Villa; Jacques J M Van Dongen; Jaap-Jan Zwaginga; Mirjam van der Burg; H Bobby Gaspar; Arjan Lankester; Frank J T Staal; Karin Pike-Overzet

doi:10.1016/j.omtm.2020.03.016

Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID

Laura Garcia-Perez, Marja van Eggermond, Lieke van Roon, Sandra A Vloemans, Martijn Cordes, Axel Schambach, Michael Rothe, Dagmar Berghuis, Chantal Lagresle-Peyrou, Marina Cavazzana, Fang Zhang, Adrian J Thrasher, Daniela Salvatori, Pauline Meij, Anna Villa, Jacques J M Van Dongen, Jaap-Jan Zwaginga, Mirjam van der Burg, H Bobby Gaspar, Arjan LankesterFrank J T Staal, Karin Pike-Overzet

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1 -/- mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.

Original language	English
Pages (from-to)	666-682
Number of pages	17
Journal	Molecular Therapy - Methods and Clinical Development
Volume	17
Early online date	31 Mar 2020
DOIs	https://doi.org/10.1016/j.omtm.2020.03.016
Publication status	Published - 12 Jun 2020
Externally published	Yes

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Garcia-Perez, L., van Eggermond, M., van Roon, L., Vloemans, S. A., Cordes, M., Schambach, A., Rothe, M., Berghuis, D., Lagresle-Peyrou, C., Cavazzana, M., Zhang, F., Thrasher, A. J., Salvatori, D., Meij, P., Villa, A., Van Dongen, J. J. M., Zwaginga, J.-J., van der Burg, M., Gaspar, H. B., ... Pike-Overzet, K. (2020). Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID. Molecular Therapy - Methods and Clinical Development, 17, 666-682. https://doi.org/10.1016/j.omtm.2020.03.016

@article{e405916e1ed4421abf8d3a6967b06cd7,

title = "Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID",

abstract = "Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1 -/- mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.",

author = "Laura Garcia-Perez and {van Eggermond}, Marja and {van Roon}, Lieke and Vloemans, {Sandra A} and Martijn Cordes and Axel Schambach and Michael Rothe and Dagmar Berghuis and Chantal Lagresle-Peyrou and Marina Cavazzana and Fang Zhang and Thrasher, {Adrian J} and Daniela Salvatori and Pauline Meij and Anna Villa and {Van Dongen}, {Jacques J M} and Jaap-Jan Zwaginga and {van der Burg}, Mirjam and Gaspar, {H Bobby} and Arjan Lankester and Staal, {Frank J T} and Karin Pike-Overzet",

note = "{\textcopyright} 2020 The Authors.",

year = "2020",

month = jun,

day = "12",

doi = "10.1016/j.omtm.2020.03.016",

language = "English",

volume = "17",

pages = "666--682",

journal = "Molecular Therapy - Methods and Clinical Development",

issn = "2329-0501",

publisher = "Cell Press",

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Garcia-Perez, L, van Eggermond, M, van Roon, L, Vloemans, SA, Cordes, M, Schambach, A, Rothe, M, Berghuis, D, Lagresle-Peyrou, C, Cavazzana, M, Zhang, F, Thrasher, AJ, Salvatori, D, Meij, P, Villa, A, Van Dongen, JJM, Zwaginga, J-J, van der Burg, M, Gaspar, HB, Lankester, A, Staal, FJT & Pike-Overzet, K 2020, 'Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID', Molecular Therapy - Methods and Clinical Development, vol. 17, pp. 666-682. https://doi.org/10.1016/j.omtm.2020.03.016

TY - JOUR

T1 - Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID

AU - Garcia-Perez, Laura

AU - van Eggermond, Marja

AU - van Roon, Lieke

AU - Vloemans, Sandra A

AU - Cordes, Martijn

AU - Schambach, Axel

AU - Rothe, Michael

AU - Berghuis, Dagmar

AU - Lagresle-Peyrou, Chantal

AU - Cavazzana, Marina

AU - Zhang, Fang

AU - Thrasher, Adrian J

AU - Salvatori, Daniela

AU - Meij, Pauline

AU - Villa, Anna

AU - Van Dongen, Jacques J M

AU - Zwaginga, Jaap-Jan

AU - van der Burg, Mirjam

AU - Gaspar, H Bobby

AU - Lankester, Arjan

AU - Staal, Frank J T

AU - Pike-Overzet, Karin

PY - 2020/6/12

Y1 - 2020/6/12

N2 - Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1 -/- mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.

AB - Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1 -/- mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.

U2 - 10.1016/j.omtm.2020.03.016

DO - 10.1016/j.omtm.2020.03.016

M3 - Article

C2 - 32322605

SN - 2329-0501

VL - 17

SP - 666

EP - 682

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

ER -

Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID

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