Hereditary pulmonary alveolar proteinosis (hPAP), a disease we previously identified, is characterized by pulmonary surfactant accumulation and respiratory failure due to alveolar macrophage (M?) dysfunction caused by mutations in the genes encoding GM-CSF receptor ? or ? (CSF2RA, CSF2RB, respectively), for which no specific pharmacotherapy currently exists. We also showed that pulmonary GM-CSF is a critical determinate of the alveolar M? phenotype and developed a novel cell transplantation approach ? pulmonary macrophage transplantation (PMT) with extraordinary therapeutic efficacy in an authentic preclinical animal model of hPAP (Csf2rb-/- mice). Our long term goal is to develop an effective definitive therapy for hPAP that is acceptable for use in children, in whom hPAP most commonly occurs. The objective here is to optimize PMT therapy using induced pluripotent stem cell-derived M?s (iPS-M?s) in hPAP model mice. The central hypothesis is that iPS-M?s can be used to generate M?s that recapitulate the phenotypic and functional characteristics of alveolar M?s, permit a deeper exploration of hPAP pathogenesis, and serve as a source of gene-repaired M?s for PMT therapy of hPAP. The rationale, based on our preliminary data, is that the proposed research will establish the feasibility and lay the groundwork for development of a new personalized medicine approach for treating children with hPAP based on autologous PMT of gene-edited iPS-M?s. This hypothesis will be tested in the following three specific aims: 1) Recapitulation of phenotypically authentic alveolar macrophages from iPS cells; 2) An authentic cellular model of hPAP pathogenesis and its correction by genome editing; 3) Pulmonary macrophage transplantation of iPS-M?s as a novel cell therapy. The approach is innovative because it differs from current gene therapy approaches to generate gene-corrected primary M?s using semi-randomly integrating lentiviral vector. The proposed research will: 1) employ advanced iPS cell technology; 2) generate human hPAP-specific iPS cells and iPS-M?s to help elucidate disease pathogenesis; 3) repair mutant alleles with a non-viral, state-of-the-art synthetic endonuclease- mediated genome-editing system (e.g., CRISPR/Cas9); and 4) demonstrate the feasibility of using iPS-M?s for a novel organ-targeted cell and gene therapy (PMT) without a requirement for myeloablation or immunosuppression. The proposed research is significant because it will: 1) identify methods to accurately recapitulate the alveolar M? phenotype from iPS cells, thereby providing a new general approach to study alveolar M?s in health and disease; 2) provide an authentic cellular model with which to study the pathogenesis of hPAP; 3) permit the optimization of a novel therapeutic strategy to simultaneously perform gene repair while minimizing safety concerns related to genotoxicity from insertional mutagenesis caused by viral vectors; and 4) demonstrate the feasibility of PMT therapy of iPSC-M?s as a novel personalized medicine approach to treat children with hPAP.
The proposed research is relevant to public health because it will establish a new disease-specific therapy for children with hereditary pulmonary alveolar proteinosis (hPAP), a rare genetic lung disease discovered by the applicant, for which no pharmacologic therapy currently exists. The proposed research will optimize a new type of gene and cell therapy ? pulmonary macrophage transplantation ? also established by the applicant in an authentic mouse model of hPAP, and will also explore alveolar macrophage function in health and disease and the pathogenesis of other surfactant-related lung diseases. Thus, the proposed research is relevant to the part of NIH?s mission that pertains to developing fundamental knowledge that will help to reduce the burden of human illness.
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