Increasing biodegradation of glycerophospholipids in pulmonary surfactant by contacting a sample of pulmonary surfactant being a component of alveolar macrophage with a lysosomal phospholipase A2 (LPLA2) protein having an amino acid sequence of SEQ ID NO:2; phospholipid catabolism disorders; lungs
Inventors
Shayman, James A. • Abe, Akira • Hiraoka, Miki
Assignees
US Department of Veterans Affairs • University of Michigan Ann Arbor
Publication Number
US-7582442-B2
Publication Date
2009-09-01
Expiration Date
2025-03-15
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Abstract
The present invention is directed to methods and compositions for improving pulmonary surfactant catabolism. More specifically, the specification describes methods and compositions for making and using a lysosomal phospholipase A2 in methods for the diagnosis, and treatment of disorders of phospholipid catabolism such as pulmonary alveolar proteinosis.
Core Innovation
The invention is directed to methods and compositions for increasing phospholipid catabolism and for the treatment of lung disease, particularly pulmonary alveolar proteinosis (PAP) and disorders of surfactant metabolism. The core innovation involves using a lysosomal phospholipase A2 (LPLA2) protein, specifically one having the amino acid sequence of SEQ ID NO:2 or biologically active fragments or variants thereof, to increase degradation of glycerophospholipids in pulmonary surfactant. This is achieved by contacting pulmonary surfactant or alveolar macrophages containing the surfactant with compositions comprising LPLA2. The LPLA2 can be administered in vivo, locally, or systemically, including by inhalant formulations.
The invention also provides diagnostic methods for pulmonary alveolar proteinosis by comparing the LPLA2 activity and/or expression in test mammals to a reference mammal, wherein decreased LPLA2 activity or expression indicates PAP. In addition, it describes methods for screening candidate substances as modulators of LPLA2 activity to identify stimulators or inhibitors of alveolar phospholipid catabolism. The invention further encompasses transgenic mice with disrupted lpla2 genes exhibiting phenotypes of phospholipidosis, useful as models for studying disorders of phospholipid catabolism and drug screening.
The problem being solved is the lack of understanding and effective treatment for phospholipid catabolism disorders, such as PAP, characterized by abnormal accumulation of phospholipids in lung tissue and alveolar macrophages leading to respiratory failure. Existing therapies like bronchioalveolar lavage and lung transplantation are invasive and often inadequate, with complications including secondary infection. There is also a need to understand drug-induced phospholipidosis caused by cationic amphiphilic drugs (CADs) and to develop therapeutic interventions that enhance surfactant degradation. The invention addresses these needs by providing LPLA2-based methods and compositions that stimulate surfactant phospholipid catabolism and offer diagnostic and therapeutic tools for phospholipid catabolism disorders.
Claims Coverage
The patent includes several independent claims focusing on methods and compositions involving LPLA2 proteins to increase degradation of pulmonary surfactant glycerophospholipids and treat phospholipid catabolism disorders.
Using LPLA2 protein to increase glycerophospholipid degradation in pulmonary surfactant
A method comprising contacting a sample containing pulmonary surfactant with a composition comprising a lysosomal phospholipase A2 (LPLA2) protein having the amino acid sequence of SEQ ID NO:2 or an enzymatically active fragment thereof, to increase degradation of glycerophospholipids in pulmonary surfactant.
The independent claims mainly cover methods of increasing degradation of pulmonary surfactant glycerophospholipids by contacting with specified LPLA2 proteins, highlighting the use of LPLA2 having SEQ ID NO:2 or active fragments to enhance phospholipid catabolism.
Stated Advantages
The invention provides alternative, less invasive therapeutic interventions for disorders of surfactant metabolism such as PAP, potentially reducing the need for bronchioalveolar lavage or lung transplantation.
LPLA2's high specificity and activity in alveolar macrophages allows targeted degradation of pulmonary surfactant phospholipids, addressing the underlying cause of phospholipid accumulation.
The transgenic mouse models facilitate studies of phospholipidosis and enable screening for agents that modulate LPLA2 activity or phospholipid catabolism.
Use of LPLA2-based compositions may overcome drug-induced phospholipidosis caused by cationic amphiphilic drugs (CADs), thereby improving safety of such therapeutics.
Documented Applications
Treatment of pulmonary alveolar proteinosis and disorders of surfactant metabolism using LPLA2 protein compositions or gene therapy to increase phospholipid catabolism.
Diagnostic methods for pulmonary alveolar proteinosis by measuring LPLA2 activity or expression in alveolar macrophages.
Screening assays for modulators of LPLA2 activity, including identification of compounds that stimulate or inhibit LPLA2 for therapeutic use or drug safety assessment.
Use of transgenic mice lacking LPLA2 as models of phospholipidosis for studying pathophysiology and evaluating therapeutic agents.
Treatment of CAD-induced phospholipidosis by administering LPLA2-based therapies to counteract enzyme inhibition by such drugs.
Combination therapies involving LPLA2 protein compositions with bronchioalveolar lavage, corticosteroids, cytokines, or other agents for lung disease management.
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