Pulmonary Alveolar Proteinosis (PAP) is a rare disease characterized by abnormal accumulation of surfactant material within the alveoli, primarily classified into acquired (autoimmune), congenital, and secondary types. Among these, autoimmune PAP (also known as idiopathic or adult-onset PAP) is the most common, accounting for approximately 90% of all cases. The typical clinical presentation includes insidiously progressive dyspnea, which may be accompanied by dry cough or scanty frothy sputum. Imaging often reveals diffuse "crazy-paving" or ground-glass opacities. Epidemiological data indicate that the prevalence of this disease is approximately 6.87 cases per million population.

 

Pathogenesis
 

Autoimmune Pulmonary Alveolar Proteinosis (aPAP) begins with the production of high-titer, neutralizing anti-Granulocyte-Macrophage Colony-Stimulating Factor (anti-GM-CSF) autoantibodies in patients. These antibodies specifically bind to GM-CSF, blocking its normal interaction with receptors on alveolar macrophages, leading to the failure of downstream key signaling pathways such as JAK-STAT. This disruption prevents alveolar macrophages from maintaining their terminal differentiation state and functional maturation, significantly impairing their ability to phagocytose and degrade alveolar surfactant material. As the dynamic balance between daily production and clearance is disrupted, surfactant components (primarily lipoproteins and SP-A, SP-D) cannot be effectively cleared, ultimately accumulating in large quantities within the alveolar spaces, forming a lipid-rich eosinophilic material. This severely impairs alveolar gas exchange function and disrupts local innate immune defenses, resulting in progressive dyspnea and increased susceptibility to opportunistic infections.
 

 

(Image placeholder: Autoimmune Pulmonary Alveolar Proteinosis)

 

Gene Therapy
 

Gene Editing Technology:
 

In some patients with hereditary PAP, repairing or replacing mutated genes (such as SFTPB, SFTPC, ABCA3) holds promise for restoring normal surfactant metabolism.

AAV Adeno-Associated Virus Vectors: Using viral vectors to deliver normal GM-CSF genes into patients to enhance alveolar macrophage function.

 

Mouse Models
 

Csf2-KO (GM-CSF Knockout) Mice: By knocking out the GM-CSF gene, these mice model the pathological state of GM-CSF deficiency, used to study the impact of alveolar macrophage dysfunction on surfactant metabolism.

Csf2rb-KO (GM-CSF Receptor β Subunit Knockout) Mice: By knocking out the β subunit of the GM-CSF receptor, these mice block the GM-CSF signaling pathway, used to study the role of GM-CSF signaling disruption in PAP pathogenesis.

 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

MingCeler Biotech can customize various PAP mouse models according to client needs, such as Csf2-KO mice and Csf2rb-KO mice. We welcome inquiries!

 

References:

[1] Wang Jiaqi, Hai Bing, Yang Yuan. Advances in the Diagnosis and Treatment of Pulmonary Alveolar Proteinosis. Chinese Journal of Clinical Medicine, 2022, 29(4): 696-700.

[2] McCarthy C, Carey BC, Trapnell BC. Autoimmune Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2022 May 1;205(9):1016-1035. doi: 10.1164/rccm.202112-2742SO. PMID: 35227171; PMCID: PMC9851473.[3] Piccoli L, Campo I, Fregni CS, Rodriguez BM, Minola A, Sallusto F, Luisetti M, Corti D, Lanzavecchia A. Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nat Commun. 2015 Jun 16;6:7375. doi: 10.1038/ncomms8375. PMID: 26077231; PMCID: PMC4477037.
 

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