At the American Thoracic Society (ATS) 2026 annual meeting on 18 May, during the B109 cellular, genetics, and developmental drivers of COPD, emphysema and sarcopenia session, investigators from Vanderbilt University and the Universities of Pittsburgh and North Carolina as well as Tgen presented compelling data identifying PABPC4 (polyadenylate-binding protein cytoplasmic-4) as a novel genetic driver of chronic obstructive pulmonary disease (COPD), linking genetic susceptibility to mitochondrial dysfunction and emphysema pathogenesis.
The study highlights a mechanistic pathway connecting non-coding genetic variants to impaired mitochondrial function in lung epithelial cells, while also introducing a first-in-class therapeutic strategy targeting RNA splicing defects.
According to the poster presented by TGen, genetic factors are estimated to account for approximately 30%–40% of COPD risk; however, the functional consequences of most susceptibility loci remain poorly understood. In the poster, researchers identified 40 non-coding variants at the PABPC4 locus with relatively high minor allele frequencies (10%–35%) that were associated with reduced lung function, increased COPD risk, and decreased PABPC4 mRNA expression in lung epithelial cells.
These findings position PABPC4 as a clinically relevant and relatively prevalent genetic contributor to COPD risk. Unlike many precision medicine targets in respiratory disease that are defined by rare variants with limited addressable populations, the relatively high frequency of these PABPC4 variants suggests a potentially sizeable patient subgroup that could be eligible for targeted intervention if a clinical-stage therapy is developed.
Mechanistically, single-cell RNA sequencing revealed that individuals carrying these variants exhibited significant dysregulation of the mitochondrial electron transport chain (ETC), a pathway critical for cellular energy production. Functional validation demonstrated that PABPC4 knockdown in lung epithelial cells impaired mitochondrial respiration, while PABPC4 knockout mice spontaneously developed emphysema, providing strong causal evidence linking PABPC4 deficiency to disease pathology.
Further investigation revealed a post-transcriptional regulatory mechanism consistent with PABPC4’s role as a poly-A binding protein. Specifically, PABPC4 deficiency resulted in increased mRNA but decreased protein levels of key ETC mediators, indicating impaired translation efficiency.
Fine-mapping identified a likely causal single nucleotide polymorphism (SNP) that disrupts pre-mRNA splicing, generating an aberrant transcript containing a premature termination codon and triggering nonsense-mediated decay. This ultimately leads to reduced PABPC4 protein levels and downstream mitochondrial dysfunction.
Importantly, the study also demonstrated early therapeutic proof-of-concept. A splice-switching antisense oligonucleotide (ss-ASO) successfully corrected the splicing defect in vitro, restoring both PABPC4 expression and ETC protein levels in lung epithelial cells derived from individuals homozygous for the causal variant. This represents a potentially transformative approach, targeting the root genetic mechanism rather than downstream symptoms.
The COPD treatment landscape remains dominated by bronchodilators and anti-inflammatory therapies, which primarily address symptoms and exacerbations rather than underlying disease mechanisms. While biologics and regenerative approaches are emerging, there are currently no approved therapies targeting mitochondrial dysfunction or genetically defined disease subtypes. As such, PABPC4 represents a compelling entry point into precision medicine for COPD, particularly given the relatively high prevalence of the identified variants.
However, translation into clinical practice will require overcoming diagnostic challenges. Identification of patients carrying the causal variant is not part of routine COPD workup, and widespread adoption of a targeted therapy would likely depend on accessible genetic screening strategies. In real-world settings, where diagnosis is largely based on spirometry and clinical presentation, implementation of routine screening may be necessary to enable patient stratification and support uptake.
Overall, these findings establish PABPC4 as a novel and mechanistically validated COPD susceptibility gene and highlight mitochondrial dysfunction as a key pathogenic axis in emphysema. The development of splice-correcting therapies introduces a differentiated and potentially disease-modifying approach, marking an important step toward precision medicine in COPD.
