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Project Background

 


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The iMACnet project builds upon an extensive body of work already generated by the partners, to large extents, in the framework of major international, national or institutional consortia funded by EU-programs (PERSIST, CELL-PID, HeMiBio, SCIDNET, CARAT, StemBANCC), the BMBF (IFB-Tx, DZL/Breath, Center for Chronic Immunodeficiency, ReGene, Galenus, TOMOspere, PID-NET), and the DFG: German Excellence Initiative (REBIRTH), Collaborative Research Centers (SFB738, SFB1040) or priority groups (SPP1230). In these and other contexts iMACnet partners have already collaborated, to:

 

i) develop and optimize gene transfer and gene editing tools for the genetic modification of iPSCs and thereof derived cells(1,2,3),

 

ii) establish the differentiation of functional macrophages from pluripotent cell sources(2,3,4),

 

iii) demonstrate proof-of-concept for the functional correction of iPSC-derived myeloid cells following gene editing and genetic repair for both target diseases(2,3), and

 

iv) provide evidence for the long-term therapeutic efficacy of the innovative concept of pulmonary macrophage transfer (PMT) in relevant in vivo disease models of herPAP(5,6).

 

Moreover, partners have contributed to major multicenter cell and gene therapy efforts(7,8) and have already established a central platform for safety analysis including karyotyping, array CGH, sequence analyses at predicted off-target sites, and whole genome sequencing(1).

  • Overall Project Objectives

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  • References

     

    1. Cathomen, T., and Ehl, S. (2014) Translating the genomic revolution - targeted genome editing in primates. The New England journal of medicine 370, 2342-2345

    2. Dreyer, A. K., Hoffmann, D., Lachmann, N., Ackermann, M., Steinemann, D., Timm, B., iler, U., Reichenbach, J., Grez, M., Moritz, T., Schambach, A., and Cathomen, T. (2015) TALEN-mediated functional correction of X-linked chronic granulomatous disease in patient-derived induced pluripotent stem cells. Biomaterials 69, 191-200

    3. Lachmann, N., Happle, C., Ackermann, M., Luttge, D., Wetzke, M., Merkert, S., Hetzel, M., Kensah, G., Jara-Avaca, M., Mucci, A., Skuljec, J., Dittrich, A. M., Pfaff, N., Brennig, S., Schambach, A., Steinemann, D., Gohring, G., Cantz, T., Martin, U., Schwerk, N., Hansen, G., and Moritz, T. (2014) Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. American journal of respiratory and critical care medicine 189, 167-182

    4. Kempf, H., Kropp, C., Olmer, R., Martin, U., and Zweigerdt, R. (2015) Cardiac differentiation of human

    pluripotent stem cells in scalable suspension culture. Nature protocols 10, 1345-1361

    5. Happle, C., Lachmann, N., Skuljec, J., Wetzke, M., Ackermann, M., Brennig, S., Mucci, A., Jirmo, A. C., Groos, S., Mirenska, A., Hennig, C., Rodt, T., Bankstahl, J. P., Schwerk, N., Moritz, T., and Hansen, G. (2014) Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis. Science translational medicine 6, 250ra113

    6. Suzuki, T., Arumugam, P., Sakagami, T., Lachmann, N., Chalk, C., Sallese, A., Abe, S., Trapnell, C., Carey, B., Moritz, T., Malik, P., Lutzko, C., Wood, R. E., and Trapnell, B. C. (2014) Pulmonary  macrophage transplantation therapy. Nature 514, 450-454

    7. Hacein-Bey-Abina, S., Pai, S. Y., Gaspar, H. B., Armant, M., Berry, C. C., Blanche, S., Bleesing, J., Blondeau, J., de Boer, H., Buckland, K. F., Caccavelli, L., Cros, G., De Oliveira, S., Fernandez, K. S., Guo, D., Harris, C. E., Hopkins, G., Lehmann, L. E., Lim, A., London, W. B., van der Loo, J. C., Malani, N., Male, F., Malik, P., Marinovic, M. A., McNicol, A. M., Moshous, D., Neven, B., Oleastro, M., Picard, C., Ritz, J., Rivat, C., Schambach, A., Shaw, K. L., Sherman, E. A., Silberstein, L. E., Six, E., Touzot, F., Tsytsykova, A., Xu-Bayford, J., Baum, C., Bushman, F. D., Fischer, A., Kohn, D. B., Filipovich, A. H., Notarangelo, L. D., Cavazzana, M., Williams, D. A., and Thrasher, A. J. (2014) A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. The New England journal of medicine 371, 1407-1417

    8. Stein, S., Ott, M. G., Schultze-Strasser, S., Jauch, A., Burwinkel, B., Kinner, A., Schmidt, M., Kramer, A., Schwable, J., Glimm, H., Koehl, U., Preiss, C., Ball, C., Martin, H., Gohring, G., Schwarzwaelder, K., Hofmann, W. K., Karakaya, K., Tchatchou, S., Yang, R., Reinecke, P., Kuhlcke, K., Schlegelberger, B., Thrasher, A. J., Hoelzer, D., Seger, R., von Kalle, C., and Grez, M. (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nature medicine 16, 198-204