Author(s) :

Vivan Patel.

Volume/Issue :

Abstract :

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with a median survival of 2.5 to 3.5 years post-diagnosis. Current FDA-approved antifibrotic therapies, including pirfenidone and nintedanib, slow disease progression, yet fail to address the underlying cellular dysfunction driving fibrosis. A key factor driving IPF pathogenesis is the senescence of alveolar type 2 (AT2) cells, the progenitor cell population that maintains and repairs the alveolar epithelium. When AT2 cells undergo the Senescence-Associated Secretory Phenotype (SASP), AT2 cells lose their regenerative capacity and secrete pro-inflammatory and pro-fibrotic factors that contribute to scarring of the lung tissue, or fibrosis. SERPINE1, the gene encoding Plasminogen Activator Inhibitor-1 (PAI-1), which is significantly upregulated in AT2 cells of IPF patients, has been mechanistically linked to senescence through inhibition of p53 degradation, activating the p53-p21-Rb cell cycle arrest pathway. Conditional knockout studies in murine models suggest that AT2-specific PAI-1 regulation suppresses senescence and weakens IPF progression, establishing SERPINE1 as a causal driver rather than a passive biomarker. This proposal outlines a gene therapy that utilizes an adeno-associated virus (AAV) vector to deliver a CRISPR interference (CRISPRi) system composed of dCas9 and a KRAB repressor domain. This system would downregulate SERPINE1 transcription without the creation of double-strand DNA breaks, offering a safer alternative to conventional CRISPR-Cas9 therapies. By targeting the upstream driver of AT2 senescence, this approach has the potential to restore alveolar regenerative capacity, reverse disease progression, and meaningfully improve IPF patient outcomes.