Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency

• Applicants: Professor Dr. Hermann Eibel; Professorin Dr. Claudia Waskow
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398018062

• Final Report Year: 2024

Final Report Abstract

Hematopoietic stem and progenitor cells were gene edited and gene correction assessed molecularly and through the gained capacity to give rise to cells of the lymphoid lineage. T cell development has been shown in in vitro culture systems and, to a lower extend, in vivo. Together, while proof of principle of gene editing of human HSPCs from primary immune deficient patients has been achieved, the efficiency of human HSPC culture and targeting conditions should be improved for further studies.

Publications

• B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation. Blood, 131(26), 2967-2977.
  Miggelbrink, Alexandra M.; Logan, Brent R.; Buckley, Rebecca H.; Parrott, Roberta E.; Dvorak, Christopher C.; Kapoor, Neena; Abdel-Azim, Hisham; Prockop, Susan E.; Shyr, David; Decaluwe, Hélène; Hanson, Imelda C.; Gillio, Alfred; Dávila, Saldaña Blachy J.; Eibel, Hermann; Hopkins, Gregory; Walter, Jolan E.; Whangbo, Jennifer S.; Kohn, Donald B.; Puck, Jennifer M. ... & Pai, Sung-Yun
  
• Epigenetic aging of human hematopoietic cells is not accelerated upon transplantation into mice. Clinical Epigenetics, 10(1).
  Frobel, Joana; Rahmig, Susann; Franzen, Julia; Waskow, Claudia & Wagner, Wolfgang
  
• Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature, 568(7753), 541-545.
  Jacome-Galarza, Christian E.; Percin, Gulce I.; Muller, James T.; Mass, Elvira; Lazarov, Tomi; Eitler, Jiri; Rauner, Martina; Yadav, Vijay K.; Crozet, Lucile; Bohm, Mathieu; Loyher, Pierre-Louis; Karsenty, Gerard; Waskow, Claudia & Geissmann, Frederic
  
• Prospective isolation of nonhematopoietic cells of the niche and their differential molecular interactions with HSCs. Blood, 134(15), 1214-1226.
  Mende, Nicole; Jolly, Adrien; Percin, Gulce I.; Günther, Marko; Rostovskaya, Maria; Krishnan, Shyam M.; Oostendorp, Robert A. J.; Dahl, Andreas; Anastassiadis, Konstantinos; Höfer, Thomas & Waskow, Claudia
  
• Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development. Nature Immunology, 21(10), 1280-1292.
  Roels, Juliette; Kuchmiy, Anna; De Decker, Matthias; Strubbe, Steven; Lavaert, Marieke; Liang, Kai Ling; Leclercq, Georges; Vandekerckhove, Bart; Van Nieuwerburgh, Filip; Van Vlierberghe, Pieter & Taghon, Tom
  
• Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development. EMBO reports, 21(5).
  Dolens, Anne‐Catherine; Durinck, Kaat; Lavaert, Marieke; Van der Meulen, Joni; Velghe, Imke; De Medts, Jelle; Weening, Karin; Roels, Juliette; De Mulder, Katrien; Volders, Pieter‐Jan; De Preter, Katleen; Kerre, Tessa; Vandekerckhove, Bart; Leclercq, Georges; Vandesompele, Jo; Mestdagh, Pieter; Van Vlierberghe, Pieter; Speleman, Frank & Taghon, Tom
  
• Efficient gene editing of human long-term hematopoietic stem cells validated by clonal tracking. Nature Biotechnology, 38(11), 1298-1308.
  Ferrari, Samuele; Jacob, Aurelien; Beretta, Stefano; Unali, Giulia; Albano, Luisa; Vavassori, Valentina; Cittaro, Davide; Lazarevic, Dejan; Brombin, Chiara; Cugnata, Federica; Kajaste-Rudnitski, Anna; Merelli, Ivan; Genovese, Pietro & Naldini, Luigi
  
• Integrated scRNA-Seq Identifies Human Postnatal Thymus Seeding Progenitors and Regulatory Dynamics of Differentiating Immature Thymocytes. Immunity, 52(6), 1088-1104.e6.
  Lavaert, Marieke; Liang, Kai Ling; Vandamme, Niels; Park, Jong-Eun; Roels, Juliette; Kowalczyk, Monica S.; Li, Bo; Ashenberg, Orr; Tabaka, Marcin; Dionne, Danielle; Tickle, Timothy L.; Slyper, Michal; Rozenblatt-Rosen, Orit; Vandekerckhove, Bart; Leclercq, Georges; Regev, Aviv; Van Vlierberghe, Pieter; Guilliams, Martin; Teichmann, Sarah A. ... & Taghon, Tom
  
• Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature, 588(7836), 157-163.
  Jayavelu, Ashok Kumar; Schnöder, Tina M.; Perner, Florian; Herzog, Carolin; Meiler, Arno; Krishnamoorthy, Gurumoorthy; Huber, Nicolas; Mohr, Juliane; Edelmann-Stephan, Bärbel; Austin, Rebecca; Brandt, Sabine; Palandri, Francesca; Schröder, Nicolas; Isermann, Berend; Edlich, Frank; Sinha, Amit U.; Ungelenk, Martin; Hübner, Christian A.; Zeiser, Robert ... & Heidel, Florian H.
  
• A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors. Cellular & Molecular Immunology, 18(7), 1662-1676.
  Moirangthem, Ranjita Devi; Ma, Kuiying; Lizot, Sabrina; Cordesse, Anne; Olivré, Juliette; de Chappedelaine, Corinne; Joshi, Akshay; Cieslak, Agata; Tchen, John; Cagnard, Nicolas; Asnafi, Vahid; Rausell, Antonio; Simons, Laura; Zuber, Julien; Taghon, Tom; Staal, Frank J. T.; Pflumio, Françoise; Six, Emmanuelle; Cavazzana, Marina ... & André, Isabelle
  
• A Novel Non-Coding Variant in DCLRE1C Results in Deregulated Splicing and Induces SCID Through the Generation of a Truncated ARTEMIS Protein That Fails to Support V(D)J Recombination and DNA Damage Repair. Frontiers in Immunology, 12.
  Strubbe, Steven; De Bruyne, Marieke; Pannicke, Ulrich; Beyls, Elien; Vandekerckhove, Bart; Leclercq, Georges; De Baere, Elfride; Bordon, Victoria; Vral, Anne; Schwarz, Klaus; Haerynck, Filomeen & Taghon, Tom
  
• BAR-Seq clonal tracking of gene-edited cells. Nature Protocols, 16(6), 2991-3025.
  Ferrari, Samuele; Beretta, Stefano; Jacob, Aurelien; Cittaro, Davide; Albano, Luisa; Merelli, Ivan; Naldini, Luigi & Genovese, Pietro
  
• Enhanced differentiation of functional human T cells in NSGW41 mice with tissue-specific expression of human interleukin-7. Leukemia, 35(12), 3561-3567.
  Coppin, Emilie; Sundarasetty, Bala Sai; Rahmig, Susann; Blume, Jonas; Verheyden, Nikita A.; Bahlmann, Franz; Ravens, Sarina; Schubert, Undine; Schmid, Janine; Ludwig, Stefan; Geissler, Katharina; Guntinas-Lichius, Orlando; von Kaisenberg, Constantin; Groten, Tanja; Platz, Alexander; Naumann, Ronald; Ludwig, Barbara; Prinz, Immo; Waskow, Claudia & Krueger, Andreas
  
• Gene Editing of Hematopoietic Stem Cells: Hopes and Hurdles Toward Clinical Translation. Frontiers in Genome Editing, 3.
  Ferrari, Samuele; Vavassori, Valentina; Canarutto, Daniele; Jacob, Aurelien; Castiello, Maria Carmina; Javed, Attya Omer & Genovese, Pietro
  
• Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper‐IgM syndrome. EMBO Molecular Medicine, 13(3).
  Vavassori, Valentina; Mercuri, Elisabetta; Marcovecchio, Genni E.; Castiello, Maria C.; Schiroli, Giulia; Albano, Luisa; Margulies, Carrie; Buquicchio, Frank; Fontana, Elena; Beretta, Stefano; Merelli, Ivan; Cappelleri, Andrea; Rancoita, Paola MV; Lougaris, Vassilios; Plebani, Alessandro; Kanariou, Maria; Lankester, Arjan; Ferrua, Francesca; Scanziani, Eugenio ... & Genovese, Pietro
  
• Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency. Frontiers in Immunology, 12.
  Ferrua, Francesca; Bortolomai, Ileana; Fontana, Elena; Di Silvestre, Dario; Rigoni, Rosita; Marcovecchio, Genni Enza; Draghici, Elena; Brambilla, Francesca; Castiello, Maria Carmina; Delfanti, Gloria; Moshous, Despina; Picard, Capucine; Taghon, Tom; Bordon, Victoria; Schulz, Ansgar S.; Schuetz, Catharina; Giliani, Silvia; Soresina, Annarosa; Gennery, Andrew R. ... & Bosticardo, Marita
  
• B Cells and COVID-19: Lessons From Patients With Agammaglobulinemia and the Study of Functional B-Cell Polymorphisms. Journal of Investigational Allergy and Clinical Immunology, 32(1), 53-55.
  Speletas, M.; Raftopoulou, S.; Farmaki, E.; Gatselis, N.; Germanidis, G.; Mouchtouri, VA; Hatzianastasiou, S.; Georgiadou, S.; Tsinti, G.; Tsachouridou, O.; Tseroni, M.; Metallidis, S.; Dalekos, G.; Eibel, H. & Hadjichristodoulou, C.
  
• BAFFR activates PI3K/AKT signaling in human naive but not in switched memory B cells through direct interactions with B cell antigen receptors. Cell Reports, 39(13), 111019.
  Sevdali, Eirini; Block, Violeta; Lataretu, Marie; Li, Huiying; Smulski, Cristian R.; Briem, Jana-Susann; Heitz, Yannic; Fischer, Beate; Ramirez, Neftali-Jose; Grimbacher, Bodo; Jäck, Hans-Martin; Voll, Reinhard E.; Hölzer, Martin; Schneider, Pascal & Eibel, Hermann
  
• Choice of template delivery mitigates the genotoxic risk and adverse impact of editing in human hematopoietic stem cells. Cell Stem Cell, 29(10), 1428-1444.e9.
  Ferrari, Samuele; Jacob, Aurelien; Cesana, Daniela; Laugel, Marianne; Beretta, Stefano; Varesi, Angelica; Unali, Giulia; Conti, Anastasia; Canarutto, Daniele; Albano, Luisa; Calabria, Andrea; Vavassori, Valentina; Cipriani, Carlo; Castiello, Maria Carmina; Esposito, Simona; Brombin, Chiara; Cugnata, Federica; Adjali, Oumeya; Ayuso, Eduard ... & Naldini, Luigi
  
• CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses. Journal of Clinical Immunology, 43(2), 391-405.
  Block, Violeta; Sevdali, Eirini; Recher, Mike; Abolhassani, Hassan; Hammarstrom, Lennart; Smulski, Cristian R.; Baronio, Manuela; Plebani, Alessandro; Proietti, Michele; Speletas, Matthaios; Warnatz, Klaus; Voll, Reinhard E.; Lougaris, Vassilios; Schneider, Pascal & Eibel, Hermann
  
• Ligand-independent oligomerization of TACI is controlled by the transmembrane domain and regulates proliferation of activated B cells. Cell Reports, 38(13), 110583.
  Smulski, Cristian R.; Zhang, Luyao; Burek, Malte; Teixidó, Rubio Ariadna; Briem, Jana-Susann; Sica, Mauricio P.; Sevdali, Eirini; Vigolo, Michele; Willen, Laure; Odermatt, Patricia; Istanbullu, Duygu; Herr, Stephanie; Cavallari, Marco; Hess, Henry; Rizzi, Marta; Eibel, Hermann & Schneider, Pascal
  
• Mobilization-based chemotherapy-free engraftment of gene-edited human hematopoietic stem cells. Cell, 185(13), 2248-2264.e21.
  Omer-Javed, Attya; Pedrazzani, Gabriele; Albano, Luisa; Ghaus, Sherash; Latroche, Claire; Manzi, Maura; Ferrari, Samuele; Fiumara, Martina; Jacob, Aurelien; Vavassori, Valentina; Nonis, Alessandro; Canarutto, Daniele & Naldini, Luigi
  
• T-Cell Progenitors As A New Immunotherapy to Bypass Hurdles of Allogeneic Hematopoietic Stem Cell Transplantation. Frontiers in Immunology, 13.
  Gaudeaux, Pierre; Moirangthem, Ranjita Devi; Bauquet, Aurélie; Simons, Laura; Joshi, Akshay; Cavazzana, Marina; Nègre, Olivier; Soheili, Shabi & André, Isabelle
  
• T-lymphoid progenitor-based immunotherapies: clinical perspectives for one and all. Cellular & Molecular Immunology, 19(12), 1435-1438.
  Gaudeaux, P.; Moirangthem, R. D.; Paillet, J.; Martin-Corredera, M.; Sadek, H.; Rault, P.; Joshi, A.; Zuber, J.; Soheili, T. S.; Negre, O. & André, I.
  
• The rs1883832 Polymorphism (CD40-1C>T) Affects the Intensity of IgA Responses after BNT162b2 Vaccination. International Journal of Molecular Sciences, 23(22), 14056.
  Speletas, Matthaios; Bakaros, Evangelos; Peristeri, Athanasia-Marina; Voulgaridi, Ioanna; Sarrou, Styliani; Paliatsa, Vassiliki; Nasika, Asimina; Tseroni, Maria; Anagnostopoulos, Lemonia; Theodoridou, Kalliopi; Kalala, Fani; Theodoridou, Aikaterini; Mouchtouri, Barbara A.; Tsiodras, Sotirios; Eibel, Hermann & Hadjichristodoulou, Christos
  
• A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Science Immunology, 8(79).
  Fornes, Oriol; Jia, Alicia; Kuehn, Hye Sun; Min, Qing; Pannicke, Ulrich; Schleussner, Nikolai; Thouenon, Romane; Yu, Zhijia; de los Angeles Astbury, María; Biggs, Catherine M.; Galicchio, Miguel; Garcia-Campos, Jorge Alberto; Gismondi, Silvina; Gonzalez, Villarreal Guadalupe; Hildebrand, Kyla J.; Hönig, Manfred; Hou, Jia; Moshous, Despina ... & Wang, Ji-Yang
  
• Intrathymic dendritic cell-biased precursors promote human T cell lineage specification through IRF8-driven transmembrane TNF. Nature Immunology, 24(3), 474-486.
  Liang, Kai Ling; Roels, Juliette; Lavaert, Marieke; Putteman, Tom; Boehme, Lena; Tilleman, Laurentijn; Velghe, Imke; Pegoretti, Valentina; Van de Walle, Inge; Sontag, Stephanie; Vandewalle, Jolien; Vandekerckhove, Bart; Leclercq, Georges; Van Vlierberghe, Pieter; Libert, Claude; Van Nieuwerburgh, Filip; Fischer, Roman; Kontermann, Roland E.; Pfizenmaier, Klaus ... & Taghon, Tom