Translational Hematology of Congenital Diseases

Objectives

The main focus of this lab is the improved understanding of human hematopoietic development and the onset of rare primary immunodeficiencies (PIDs) to develop novel therapeutic strategies. In using multipotent and pluripotent stem cell sources, the lab of Dr. Lachmann investigates factors that are important for hematopoietic specification and the generation of new therapeutic target cells, which can be used in future clinical trials.

Research Focus

The concept of blood formation as a hierarchical process, referred to as hematopoiesis, is fundamentally based on the existence of multipotent hematopoietic stem cells (HSCs) that are derived from pluripotent stem cells (PSC). Different intra- and extracellular factors have been proven to be critical for this process, as their malfunction is able to cause defects in the formation of blood cells. To this end, the main interest of this lab is to investigate PIDs such as Pulmonary Alveolar Proteinosis (PAP) or Mendelian Susceptibility to Mycobacterial Disease (MSMD) in order to evaluate novel cell replacement therapies. Therefore, we combine gene therapy strategies such as viral vectors or precise genome editing tools (TALEN or CRISP/RCas) with multipotent or pluripotent cell derived hematopoietic cells to improve the overall outcome of the afore mentioned diseases. In order to improve the generation of novel PSC-derived hematopoietic cells that are suitable for cell replacement therapies, innovative protocols for human hematopoietic differentiation are also evaluated. Here, the modification of cytokines, miRNAs, or transcription factors plays the central role for further optimization of protocols that can be performed in large-scale. Close collaborations to medical universities or hospitals such as Uniklinikum Dresden, Uniklinikum Ulm or the Cincinnati Childrens Hospital would allow for the subsequent clinical translation of new and innovative therapeutic strategies. 

Collaborations

Off-campus:

  • Prof. Bruce Trapnell and Prof. Takuji Suzuki (Cincinnati Childrens Hospital Medical Center, Cincinnati, USA)
  • Dr. Michael Grimley (Cincinnati Childrens Hospital Medical Center, Cincinnati, USA)
  • Prof. Frederic Geissmann (King`s College London, UK and Sloan Kettering Memorial Cancer Center, NYC, USA)
  • Prof. Jean-Laurent Casanova (Rockefeller University, NYC, USA and Necker Hospital, Paris, France)
  • Prof. George Lacaud (Cancer Research UK Manchester Institute, Manchester, UK)
  • Dr. Bernhard Gentner (San Raffaele Hospital, Telethon Institute for Gene Therapy)
  • Prof. Toni Cathomen (Institut für Zell- und Gentherapie, Universitätsklinikum Freiburg)
  • Prof. Joachim Rössler (Universitätsklinikum Dresden)
  • Prof. Ansgar Schulz (Universitätsklinikum Ulm)
  • Prof. Carlos Guzmán (Helmholtz, Center for Infection Research, Braunschweig)

On-campus:

Awards

  • 2015: Abstract Achievement Award, American Society of Hematology (ASH) (Orlando, FL, USA))
  • 2015: Fellowship for Interdisciplinary Sciences, Joachim Herz Stiftung
  • 2015: Best-Poster-Award, German Stem Cell Network (GSCN, Frankfurt am Main, Germany)
  • 2015: “DGP Forschungspreis für klinische Forschung” Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin e.V. (DGP) together with Dr. med. Christine Happle, Berlin, Germany
  • 2015: Klaus Betke Fellowship, 2nd Klaus Betke Symposium, Munich, Germany
  • 2014: Top Abstract Award & Best Translational Research Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO), Hamburg, Germany
  • 2014 Selected as top abstract at “Presidential Symposium” American Society for Gene and Cell Therapy (ASGCT); Washington D.C. (USA)
  • 2014-2016 Young Academy Fellowship Hannover Medical School
  • 2013 Eva-Luise Köhler Forschungspreis für seltene Erkrankungen 2013 (Eva-Luise Köhler research award for rare diseases 2013) together with Prof. Gesine Hansen, Prof. Thomas Moritz and Dr. Christine Happle; Eva Luise und Horst Köhler Stiftung, Allianz Chronischer Seltener Erkrankungen; Berlin (Germany)
  • 2012-2013 Hochschulinterne Leistungsförderung (HiLF-Award), Hannover Medical School
  • 2011-2015 Numerous Travel Awards (American Society for Gene and Cell Therapy ASGCT, European Society for Gene and Cell Therapy; ESGCT, International Society for Stem Cell Research ISSCR (Vancouver), German Stem Cell Network GSCN (Heidelberg)

Teaching

  • Medicine (Hannover Medical School): Gene Therapy of Primary Immunodeficincies
  • PhD programme ‘Regenerative Sciences’(Hannover Medical School): Animal Models of Human Diseases 2
  • M.Sc. Biomedicine (Hannover Medical School): Mentoring programme
  • B.Sc. Biology (Leibniz University Hannover: Strategies of Gene Therapy for Rare Immunodeficiencies

Scientific Activities

  • Initiator and founder of “REBIRTH – Goes Back to School”; Scientific talks for students) Scientific interactions with: Gymnasium Burgdorf, Robert Koch Gymnasium in Clausthal Zellerfeld, Gymnasium in Wolfsburg, IGS Sarstedt, St. Ursula-Schule Gymnasium Hannover
  • Initiator of “Rebirth v2.0“ Interaction of Rebirth and Burgdorf Gymnasium for “Jugend forscht”
  • Lecturer (Katholische Kirche Niedersachsen for Stem Cells in Regenerative Sciences)
  • Member of “Ethikuniversität an der Medizinischen Hochschule Hannover”
  • Member in the REBIRTH organizing committee for the IdeenExpo, Hannover (Germany)

Selected Publications

Happle C*, Lachmann N*, Ackermann M, Mirenska A, Göhring G, Thomey K, Mucci A, Hetzel M, Glomb T, Suzuki T, Chalk C, Glage S, Dittrich-Breiholz O, Trapnell B, Moritz t, Hansen G „Pulmonary Transplantation of human iPSC-derived Macrophages ameliorates Pulmonary Alveolar Proteinosis“ Am J Respir Crit Care Med. 2018 *contributed equally

Hetzel M, Mucci A, Blank P, Nguyen AHH, Schiller J, Halle O, Kühnel M-P, Billig S, Meineke R, Brand D, Herder V, Baumgärtner W, Bange F-C, Goethe R, Jonigk D, Förster R, Gentner B, Casanova J-L, Bustamante J, Schambach A, Kalinke U, Lachmann N. Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. Blood. 2018;131(5):533.

Lachmann N*, Czarnecki K*, Brennig S, Phaltane P, Heise M, Heinz N, Kempf H, Dilloo D, Kaever V, Schambach A, Heuser M, Moritz T “Deoxycytidine-kinase (dCK) knock-down as a novel myeloprotective strategy in the context of fludarabine, cytarabine, or cladribine therapy” Leukemia. 2015 *contributed equally

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 RE, Trapnell BC „ Pulmonary macrophage transplantation therapy“ Nature 2014

Happle C*, Lachmann N*, Skuljec J, Wetzke M, Ackermann M, Brennig S, Mucci A, Jirmo AC, Groos S, Mirenska A, Hennig C, Rodt T, Bankstahl JP, Schwerk N, Moritz T, Hansen G. „Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis„ Science Transl Med. 2014 *contributed equally

Lachmann N*, Happle C*, Lüttge D, Wetzke M, Merkert S, Ackermann M, Kensah J, Jara-Avaca M, Mucci A, Skuljec J, Dittrich AM, Pfaff N, Brennig S, Schambach A, Steinemann D, Göhring G, Cantz T, Martin U, Schwerk N, Hansen G, Moritz T “Gene correction of human induced Pluripotent Stem Cells repairs the cellular phenotype in Pulmonary Alveolar Proteinosis” Am J Respir Crit Care Med. 2014 *contributed equally

Publications

2013 - ongoing

2018

Happle C*, Lachmann N*, Ackermann M, Mirenska A, Göhring G, Thomey K, Mucci A, Hetzel M, Glomb T, Suzuki T, Chalk C, Glage S, Dittrich-Breiholz O, Trapnell B, Moritz t, Hansen G „Pulmonary Transplantation of human iPSC-derived Macrophages ameliorates Pulmonary Alveolar Proteinosis“ Am J Respir Crit Care Med. 2018 *contributed equally

Hetzel M, Mucci A, Blank P, Nguyen AHH, Schiller J, Halle O, Kühnel M-P, Billig S, Meineke R, Brand D, Herder V, Baumgärtner W, Bange F-C, Goethe R, Jonigk D, Förster R, Gentner B, Casanova J-L, Bustamante J, Schambach A, Kalinke U, Lachmann N. Hematopoietic stem cell gene therapy for IFNγR1 deficiency protects mice from mycobacterial infections. Blood. 2018;131(5):533.

Neehus AL, Lam J, Haake K, Merkert S, Schmidt N, Mucci A, Ackermann M, Schubert M, Happle C, Kuhnel MP, Blank P, Philipp F, Goethe R, Jonigk D, Martin U, Kalinke U, Baumann U, Schambach A, Roesler J, Lachmann N. Impaired IFNgamma-Signaling and Mycobacterial Clearance in IFNgammaR1-Deficient Human iPSC-Derived Macrophages. Stem Cell Reports. 2017. Epub 2017/12/19.

2017

Pittermann E, Lachmann N, MacLean G, Emmrich S, Ackermann M, Göhring G, Schlegelberger B, Welte K, Schambach A, Heckl D, Orkin SH, Cantz T, Klusmann J-H. Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells. Blood Adv. 2017 2017/06//; 1(14):[903-14 pp.

Kuhn A, Ackermann M, Mussolino C, Cathomen T, Lachmann N, Moritz T. TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis. Sci Rep. 2017/11/11 ed2017. p. 15195.

Hartmann D, Fiedler J, Sonnenschein K, Just A, Pfanne A, Zimmer K, Remke J, Foinquinos A, Butzlaff M, Schimmel K, Maegdefessel L, Hilfiker-Kleiner D, Lachmann N, Schober A, Froese N, Heineke J, Bauersachs J, Batkai S, Thum T. MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease. Circulation. 2016/10/27 ed2016. p. 1973-90.

Hetzel M, Suzuki T, Hashtchin AR, Arumugam P, Carey B, Schwabbauer M, Kuhn A, Meyer J, Schambach A, Van Der Loo J, Moritz T, Trapnell BC, Lachmann N. Function and Safety of Lentivirus-Mediated Gene Transfer for CSF2RA-Deficiency. Hum Gene Ther Methods. 2017/09/01 ed2017.

Kunkiel J, Godecke N, Ackermann M, Hoffmann D, Schambach A, Lachmann N, Wirth D, Moritz T. The CpG-sites of the CBX3 ubiquitous chromatin opening element are critical structural determinants for the anti-silencing function. Sci Rep. 2017/08/13 ed2017. p. 7919.

Ackermann M, Kuhn A, Kunkiel J, Merkert S, Martin U, Moritz T, Lachmann N. Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells. Transfus Med Hemother. 2017/06/20 ed2017. p. 135-42.

Lopez-Rodriguez E, Gay-Jordi G, Mucci A, Lachmann N, Serrano-Mollar A. Lung surfactant metabolism: early in life, early in disease and target in cell therapy. Cell Tissue Res. 2016/10/27 ed2017. p. 721-35.

2016

Skuljec J, Cabanski M, Surdziel E, Lachmann N, Brennig S, Pul R, Jirmo AC, Habener A, Visic J, Daluge K, Hennig C, Moritz T, Happle C, Hansen G. Monocyte/macrophage lineage commitment and distribution are affected by the lack of regulatory T cells in scurfy mice. Eur J Immunol. 2016;46(7):1656-68.

Mucci A, Kunkiel J, Suzuki T, Brennig S, Glage S, Kuhnel MP, Ackermann M, Happle C, Kuhn A, Schambach A, Trapnell BC, Hansen G, Moritz T, Lachmann N. Murine iPSC-Derived Macrophages as a Tool for Disease Modeling of Hereditary Pulmonary Alveolar Proteinosis due to Csf2rb Deficiency. Stem cell reports. 2016;7(2):292-305.

Hoepfner J, Kleinsorge M, Papp O, Ackermann M, Alfken S, Rinas U, Solodenko W, Kirschning A, Sgodda M, Cantz T. Biphasic modulation of Wnt signaling supports efficient foregut endoderm formation from human pluripotent stem cells. Cell Biol Int. 2016;40(5):534-48.

Borger AK, Eicke D, Wolf C, Gras C, Aufderbeck S, Schulze K, Engels L, Eiz-Vesper B, Schambach A, Guzman CA, Lachmann N, Moritz T, Martin U, Blasczyk R, Figueiredo C. Generation of HLA-universal iPSCs-derived megakaryocytes and platelets for survival under refractoriness conditions. Molecular medicine. 2016;22.

2015

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

Brennig S, Lachmann N, Buchegger T, Hetzel M, Schambach A, Moritz T. Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1). Journal of experimental & clinical cancer research : CR. 2015;34:148.

2006 - 2012

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