Thursday, May 15, 2025
5/15/2025
Alveolar injury and repair in Pompe Disease - Project Summary/Abstract Pompe disease is a rare autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA) – a lysosomal enzyme that hydrolyzes glycogen. GAA deficiency results in glycogen accumulation in the lysosomes of cardiac, skeletal, and smooth muscle as well as motor neurons1-3. Despite treatment with enzyme replacement therapy (ERT), many patients develop recurrent respiratory infections, restrictive lung disease, and respiratory insufficiency4,5. As a result, respiratory failure is still the leading cause of death6. Respiratory compromise was previously attributed to failure to protect the upper airway, diaphragm muscle weakness, motor neuron pathology, and airway smooth muscle pathology7-10. However, recent findings from our laboratory identified significant pathology in alveolar type 1 and type 2 (AT1 and AT2) cells as a result of GAA deficiency and glycogen accumulation. Specifically, we found that GAA deficiency in Pompe disease resulted in engorged lysosomes which significantly disrupted AT1 and AT2 cellular architecture. Lysosomes are an essential component of autophagy which is important for maintaining cellular homeostasis. We also found that GAA deficiency resulted in reduced surfactant protein D gene (SP-D) expression and abnormal surfactant accumulation11. Building on these novel findings, the central hypothesis of this proposal is that GAA deficiency disrupts alveolar repair after lung injury and impairs autophagy, and AAV-GAA gene therapy will enhance lung damage repair and reverse alveolar pathology. Three specific aims will be accomplished using the Pompe disease mouse – the Gaa-/- mouse. Aim 1 will determine if Gaa-/- AT2 cells successfully differentiate, repair and repopulate damaged alveolar cells following lung injury. Aim 2 will elucidate the impact of GAA deficiency on autophagy and cellular homeostasis in AT2 cells. Finally, aim 3 will treat alveolar pathology using AAV therapy and to combine airway and systemic therapy to treat the global disease. The proposed experiments will evaluate AT2 cellular function in alveolar repair following a lung injury. We will use a series of ex vivo and in vivo studies, biochemical and histological assessments of lungs, as well as functional and behavioral studies. This proposal will uniquely combine the respiratory physiology and Pompe disease mouse model experience of the PI (ElMallah), with Co-PI Tata’s alveolar stem cell, genetic and epigenetic expertise. This work is innovative because the impact of GAA deficiency on alveolar repair following lung injury has not been evaluated and will provide clinically relevant information for future therapeutic interventions. Finally, defining the impact of GAA deficiency on alveolar differentiation and proliferation in Pompe disease will impact clinical care and inform clinicians about deficits in lung repair following infectious and aspiration injuries.
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