Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis

被引：9

作者：

Hetzel, Miriam ^{[1
]}

Lopez-Rodriguez, Elena ^{[2
]}

Mucci, Adele ^{[1
]}

Ha Nguyen, Ariane Hai ^{[1
]}

Suzuki, Takuji ^{[3
,4
]}

Shima, Kenjiro ^{[3
]}

Buchegger, Theresa ^{[1
]}

Dettmer, Sabine ^{[5
]}

Rodt, Thomas ^{[5
]}

Bankstahl, Jens P. ^{[6
]}

Malik, Punam ^{[7
]}

Knudsen, Lars ^{[2
]}

Schambach, Axel ^{[1
,8
]}

Hansen, Gesine ^{[9
]}

Trapnell, Bruce C. ^{[3
,10
]}

Lachmann, Nico ^{[1
]}

Moritz, Thomas ^{[1
]}

机构：

[1] Hannover Med Sch, Inst Expt Hematol, Hannover, Germany

[2] Hannover Med Sch, Inst Funct & Appl Anat, Hannover, Germany

[3] Cincinnati Childrens Hosp Med Ctr, Div Pulm Biol, Translat Pulm Sci Ctr, Cincinnati, OH 45229 USA

[4] Jichi Med Univ, Div Pulm Med, Shimotsukeshi, Tochigi, Japan

[5] Hannover Med Sch, Dept Radiol, Hannover, Germany

[6] Hannover Med Sch, Dept Nucl Med, Hannover, Germany

[7] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, CBDI, Cincinnati, OH 45229 USA

[8] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[9] Hannover Med Sch, Dept Pediat Allergol & Neonatol, Hannover, Germany

[10] Childrens Hosp Med Ctr, Div Pulm Med, Cincinnati, OH USA

来源：

HAEMATOLOGICA | 2020年 / 105卷 / 04期

关键词：

RECEPTOR-DEFICIENT MICE; MACROPHAGES; TRANSPLANTATION; LIFE; PROLIFERATION; ACTIVATION; COLONY;

D O I：

10.3324/haematol.2018.214866

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using Csf2rb(-/-) mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff' material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c(+)/SiglecF(- )cells in the lungs from a CD11c(-)/SiglecF(+) progenitor population within four weeks after transplantation. Based on these data, we suggest hematopoietic stem cellbased gene therapy as an effective and cause-directed treatment approach for herPAP.

引用

页码：1147 / 1157

页数：11

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