Dataset Information

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.

SUBMITTER: Garcia-Perez L

PROVIDER: S-EPMC7163047 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

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

Molecular therapy. Methods & clinical development 20200331

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 ...[more]

PMID: 32322605

Similar Datasets

Project description:Within the last decade there have been several severe combined immunodeficient (SCID) pig models discovered or genetically engineered. The animals have mutations in ARTEMIS, IL2RG, or RAG1/2 genes, or combinations thereof, providing SCID pigs with NK cells, but deficient in T and B cells, or deficient in NK, T, and B cells for research studies. Biocontainment facilities and positive pressure isolators are developed to limit pathogen exposure and prolong the life of SCID pigs. Raising SCID pigs in such facilities allows for completion of long-term studies such as xenotransplantation of human cells. Ectopically injected human cancer cell lines develop into tumors in SCID pigs, thus providing a human-sized in vivo model for evaluating imaging methods to improve cancer detection and therapeutic research and development. Immunocompromised pigs have the potential to be immunologically humanized by xenotransplantation with human hematopoietic stem cells, peripheral blood leukocytes, or fetal tissue. These cells can be introduced through various routes including injection into fetal liver or the intraperitoneal (IP) space, or into piglets by intravenous, IP, and intraosseous administration. The development and maintenance of transplanted human immune cells would be initially (at least) dependent on immune signaling from swine cells. Compared to mice, swine share higher homology in immune related genes with humans. We hypothesize that the SCID pig may be able to support improved engraftment and differentiation of a wide range of human immune cells as compared to equivalent mouse models. Humanization of SCID pigs would thus provide a valuable model system for researchers to study interactions between human tumor and human immune cells. Additionally, as the SCID pig model is further developed, it may be possible to develop patient-derived xenograft models for individualized therapy and drug testing. We thus theorize that the individualized therapeutic approach would be significantly improved with a humanized SCID pig due to similarities in size, metabolism, and physiology. In all, porcine SCID models have significant potential as an excellent preclinical animal model for therapeutic testing.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure