B109-10 PABPC4: A Genetic Driver of Mitochondrial Dysfunction and Emphysema in COPD Targeted by a First-in-Class Therapeutic Agent

Rationale Genetic factors account for ∼30-40% of COPD risk, yet the mechanisms linking susceptibility loci to disease pathogenesis remain poorly defined. We investigated how a novel susceptibility locus near the PABPC4 (Polyadenylate-Binding Protein Cytoplasmic-4) gene contributes to COPD pathogenesis. Methods and Results We identified 40 non-coding variants at the PABPC4 locus that were highly prevalent (minor allele frequency 10-35%) and associated with reduced lung function, increased COPD risk, and lower PABPC4 mRNA levels in the lung epithelial compartment. Single-cell RNA sequencing revealed that the top dysregulated pathway in individuals homozygous vs. wild-type for these variants was the mitochondrial electron transport chain (total n=114). Similarly, PABPC4 knockdown in lung epithelial cells via RNAi disrupted the electron transport chain pathway and impaired mitochondrial function, as assessed by Seahorse assays. Additionally, PABPC4 knockout mice spontaneously developed emphysema, underscoring the gene’s causal role in the pathogenesis of emphysema. Mechanistically, PABPC4 deficiency increased mRNA but decreased protein levels of electron transport chain mediators, indicating post-transcriptional regulation consistent with its role as a poly-A binding protein. Fine-mapping identified a likely causal SNP that disrupts PABPC4 pre-mRNA splicing, generating an aberrant exon containing a premature termination codon that triggered nonsense-mediated decay (Fig 1). Importantly, a first-in-class splice-switching anti-sense oligonucleotide (ss-ASO) corrected this splicing defect to restore PABPC4 expression and electron transport chain mediator protein levels in lung epithelial cells from an individual homozygous for the causal variant in vitro. Conclusions PABPC4 is a novel COPD susceptibility gene that regulates mitochondrial function in lung epithelia through post-transcriptional control of the electron transport chain. The causal variant at the PABPC4 locus leads to splicing-mediated loss of PABPC4, mitochondrial dysfunction, and emphysema. A first-in-class therapeutic agent that corrects this splicing defect may represent a novel treatment for mitochondrial dysfunction in COPD. Funding R01HL153400, R01HL124233, R01HL179364, American Lung Association This abstract is funded by: American Lung Association