Immungenetik | Universitätsklinikum Tübingen

AG “Cell and Gene Therapy“

Research Topics

Gene correction of human b-thalassemic hematopoietic stem cells using CRISPR/Cas9 mechanism
CRISPR/Cas9-boosted improvements in CAR-T and CAR-NK cell-based immunotherapy for cancer treatment
Gene-engineering of monoclonal CHO cell lines using FluidFM® nano-injection and CRISPR/Cas9
Hematopoietic stem cell gene therapy with CRISPR/Cas9 mRNA and AAV6 vector in metachromatic leukodystrophy

Funding and Publication

Lead

frontend.sr-only_#{element.contextual_1.children.icon}: PD Dr. med. Dr. rer. nat. Dipl. Biol. Markus Mezger Group leader

frontend.sr-only_#{element.contextual_1.children.icon}: 07071 29-80879

E-Mail-Adresse: markus.mezger@med.uni-tuebingen.de

frontend.sr-only_#{element.contextual_1.children.icon}: Dr. rer. nat. Justin Selvaraj Junior group leader

E-Mail-Adresse: justin.selvaraj@med.uni-tuebingen.de

frontend.sr-only_#{element.contextual_1.children.icon}: Dr. Tahereh Mohammadian Gol Postdoc

E-Mail-Adresse: Tahereh.Mohammadian-Gol@med.uni-tuebingen.de

Gene therapy

Our team is primarily working in the field of hematopoietic stem cell transplanation (HSCT). By utilizing various cell and gene therapy approaches, we aim to develop novel gene therapy modalities for β- hemoglobinopathies (β-thalassemia, sickle cell disease), cancer immunotherapy, and rare diseases including metachromatic leukodystrophy and immunodeficiency. Our technologies include lentiviral (LV) and Adeno-associated virus (AAV) gene transfer, mRNA therapeutics, adoptive immune cell therapy, genome editing and gene correction using CRISPR / Cas9 system.

(Lamsfus Calle et al., 2019, Blood Reviews, https://doi.org/10.1016/j.blre.2019.100641)

(Ureña Bailén et al., 2019, Briefings in Functional Genomics, https://doi.org/10.1093/bfgp/elz039)

(Daniel Moreno et al., 2019, Bone Marrow Transplantation, https://doi.org/10.1038/s41409-019-0510-8)

Immunomodulation

As we focus on HSCT, in our research we are addressing a major adverse effect called graft versus host disease (GvHD), a serious complication after allogeneic stem cell transplantation. To achieve this goal, we are utilizing donor’s immune cells including mesenchymal stromal cells, myeloid suppressor cells and regulatory T cells to better control immune reaction of the graft through immune modulation.

KIR Genotyping

We are employing state-of-the-art technologies including sequencing, fragment analysis, droplet digital PCR (ddPCR) and developing innovative methods in order to identify optimized stem cell donors, and improving previous diagnostic routine assays for chimerism analysis, KIR genotyping and minimal residual disease (MRD) analysis.

Laboratory for chimerism analysis and KIR genotyping

Funding and Publication

Fortüne Programm Tübingen
Clinician Scientist Programm Tübingen
Deutsche José Carreras Leukämie-Stiftung e. V.
Förderverein für krebskranke Kinder Tübingen e.V.
Manchot Stiftung
DEBRA Austria
Bundesministerium für Bildung und Forschung
Deutsches Zentrum für Infektionsforschung
Stefan-Morsch Stiftung

Ureña-Bailén G*, Block M*, Grandi T, Aivazidou F, Quednau J, Krenz D, Daniel-Moreno A, Lamsfus-Calle A, Epting T, Handgretinger R, Wild S*, Mezger M* (2023) Automated Good Manufacturing Practice-Compatible CRISPR-Cas9 Editing of Hematopoietic Stem and Progenitor Cells for Clinical Treatment of β-Hemoglobinopathies. The CRISPR Journal 6(1):5-16. doi: 10.1089/crispr.2022.0086
Hou Y, Ureña-Bailén G, Mohammadian Gol T, Gratz PG, Gratz HP, Roig-Merino A, Antony JS, Lamsfus-Calle A, Daniel-Moreno A, Handgretinger R, Mezger M (2022) Challenges in Gene Therapy for Somatic Reverted Mosaicism of X-linked Combined Immunodeficiency by CRISPR/Cas9 and Prime Editing. Genes 13(12):2348. doi: 10.3390/genes13122348
Ureña-Bailén G, Dobrowolski JM, Hou Y, Dirlam A, Roig-Merino A, Schleicher S, Atar D, Seitz C, Feucht J, Antony JS, Mohammadian-Gol T, Handgretinger R, Mezger M (2022) Preclinical evaluation of CRISPR-edited CAR-NK-92 cells for off-the-shelf treatment of AML and B-ALL. International Journal of Molecular Sciences 23(21):12828. doi: 10.3390/ijms232112828
Antony J*, Daniel-Moreno A*, Lamsfus-Calle A, Raju J, Kaftancioglu M, Ureña-Bailén G, Rottenberger J, Hou Y, Santhanakumaran V, Lee J-H, Heumos L, Böhringer J, Krägeloh-Mann I, Handgretinger R, Mezger M (2022) A mutation-agnostic hematopoietic stem cell gene therapy for metachromatic leukodystrophy. The CRISPR Journal 5(1):66-79. doi: 10.1089/crispr.2021.0075
Hou Y, Gratz HP, Ureña-Bailén G, Gratz PG, Schilbach-Stückle K, Renno T, Güngör D, Mader DA, Malenke E, Antony JS, Handgretinger R, Mezger M (2021) Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency. Genes 13(1):35. doi.org/10.3390/genes13010035
Lamsfus-Calle A*, Daniel-Moreno A*, Ureña-Bailén G, Rottenberger J, Raju J, Epting T, Marciano S, Heumos L, Baskaran P, Antony J, Handgretinger R, Mezger M (2021) Universal gene correction approaches for β-hemoglobinopathies using CRISPR-Cas9 and AAV6 donor templates. The CRISPR Journal 4(2):207-222. doi: 10.1089/crispr.2020.0141
Lamsfus-Calle A*, Daniel-Moreno A*, Antony JS, Epting T, Heumos L, Baskaran P, Admar J, Casadei N, Latifi N, Siegmund D, Kormann M, Handgretinger R, Mezger M (2020) Comparative targeting analysis of KLF1, BCL11A and HBG1/2 in CD34+ HSPCs by CRISPR/Cas9 for the induction of fetal hemoglobin. Nature Scientific Reports 10(1):10133. doi: 10.1038/s41598-020-66309-x.
Lamsfus-Calle A*, Daniel-Moreno A*, Ureña-Bailén G, Raju J, Antony J, Handgretinger R, Mezger M (2019) Hematopoietic Stem Cell Gene Therapy: The optimal use of Lentivirus and Gene Editing Approaches. Blood Reviews 15:100641. doi: 10.1016/j.blre.2019.100641
Oevermann L*, Michaelis S*, Mezger M*, Lang P, Toporski J, Bertaina A, Zecca M, Moretta L, Locatelli F*, Handgretinger R* (2014) KIR B haplotype donors confer a reduced risk of relapse after haploidentical transplantation in children with acute lymphoblastic leukemia. Blood 124: 2744-2747
Mezger M, Steffens M, Beyer M, Manger C, Eberle J, Toliat MR, Wienker TF, Ljungman P, Hebart H, Dornbusch HJ, Einsele H, Loeffler J (2008) Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood 111: 534-536