Evaluating the Use of iPSC-Derived Models in Understanding the Pathogenesis of Childhood Interstitial Lung Disease.

Rationale: Genetic testing has significantly improved the diagnosis of childhood interstitial lung diseases (chILD), which have long challenged clinicians due to their heterogeneity and poor characterization. It is now imperative to study variants of unknown significance (VUS) to identify pathogenic mutations to optimize diagnosis and screening in patients. Furthermore, the limited treatment options for patients with chILD worsen patient outcomes. Induced pluripotent stem cell (iPSC)-derived models could be a tool to understand the effect of novel VUS and discover new therapeutic interventions.

Objective: This review seeks to evaluate the fidelity of iPSC-derived models to recapitulate the pathogenic processes of chILD and test therapeutic interventions.

Methods: This paper performs a systematic search over three databases to identify iPSC-derived models studying disease-causing mutations in pediatric patients with chILD and Hermansky-Pudlak Syndrome.

Results: Of the 1452 papers initially reviewed, eight papers met the inclusion criteria using iPSC-derived models to study genetic variants. The diseases covered included common manifestations of chILDs such as surfactant protein deficiencies and hereditary pulmonary alveolar proteinosis, as well as fibrotic disorders like Hermansky-Pudlak Syndrome. These models recapitulated patient histology and key pathogenic features reported in the literature, delivering mechanistic insights into these conditions. Some papers also explored the efficacy of novel treatments, such as gene therapy.

Conclusions: iPSC-derived models can mimic aspects of human lung responses to provide a platform for disease modeling and therapeutic testing in chILD. There are opportunities to develop more complex multi-cellular models and for the study of a wider range of variants using these tools.