Genetically corrected induced pluripotent stem cells-derived tissue-macrophages as an innovative therapy approach of hereditary Pulmonary Alveolar proteinosis (PAP)

• Applicant: Professor Dr. Nico Lachmann
• Subject Area: Hematology, Oncology ; Pneumology, Thoracic Surgery
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275410142

Due to their unlimited self-renewal- as well as differentiation potential, induced pluripotent stem cells became a highly desirable cell type for regenerative medicine, recognized by the nobel-prize for medicine or physiology in 2012. Besides their differentiation potential towards cells of the endo- or ectodermal lineage, also their differentiation potential towards cells of the mesoderm- in particular hematopoietic lineage opens a new therapeutic era for rare-hematological disorders. Although differentiation of iPSC towards mature cells of the hematopoietic system has been proven to be feasible, however, generation of bona fide hematopoietic stem cells with long term repopulating potential remains elusive as of now. In this line, generation of functional mature cells from pluripotent stem cells sources may represent a novel way for cell and gene therapy approaches. Here, the generation of monocyte/macrophages might be an attractive target cell, as these cells are known to be key players in various tissues. Especially alveolar macrophages are of great importance as these cells represent the first line of host-defense in the lungs and are important for lung homeostasis. Mutations in the GM-CSF receptor genes (CSF2RA and CSF2RB) lead to impaired alveolar macrophages and to the life-threatening disease pulmonary alveolar proteinosis (PAP). PAP is characterized by massive protein accumulation in the lungs leading to progressive respiratory failure and a high susceptibility for pulmonary infections. As no curative treatment is available to-date, new therapeutic strategies are highly desirable. In order to investigate novel therapeutic options, we have evaluated the feasibility of organotropic transplantation of hematopoietic stem cell derived macrophages in a murine as well as in a humanized PAP mouse model (manuscript attached).Combining the differentiation potential of iPSC towards macrophages with the field of gene therapy and the pathophysiology of PAP, may lead to a highly innovative treatment option for PAP by a pulmonary-cell-transplant (PCT) of genetically corrected, iPSC derived monocyte/macrophages. Here, genetically corrected iPSC derived macrophages will be investigated in two highly relevant PAP-mouse models for their innovative use in organotropic transplantation. In a clinical transfer scenario, these iPSC cells could be generated in a patient specific manner, genetically corrected and differentiated towards hematopoietic cells of patient origin. The so generated cells would not only allow for a potential long-lasting clinical benefit for the PAP patients, but would further abrogate the waiting time for suitable HLA-matched donors or further decrease the risk of immune rejection. Taken together, this approach would not only increase the quality of life of PAP patients, but would also pave the way for cell-therapeutics using mature cells, such as macrophages, rather than stem cells derived from pluripotent stem cell sources.

• DFG Programme: Research Grants