Optimization of gene therapy for pulmonary fibrosis in Hermansky-Pudlak Syndrome Type 1 using AAV Vectors in mouse models

Authors

• MN LaRoche
• G Nieto
• M Behan
• M Hossain
• MCV Malicdan
• WA Gahl

Abstract

Hermansky-Pudlak Syndrome type 1 (HPS-1) is a rare autosomal recessive multisystemic
disease caused by loss-of-function mutations in the HPS1 gene. A hallmark of HPS-1 is adult-onset pulmonary fibrosis (HPS1-PF), which is invariably fatal without intervention. Currently, lung transplantation is the only treatment for HPS1-PF, though it carries substantial morbidity. To explore alternative therapeutic avenues, we engineered two mouse models using CRISPR/Cas technology: an Hps1 knockout (HPS1Δ/Δ) mouse model which targets the promoter region through intron 3, and a humanized knock-in (HPS1 dup/dup ) mouse model with the common human 16 base pair duplication HPS1 mutation in exon 15. We employed adeno-associated virus (AAV) vectors for gene delivery, administering the human HPS1 gene both intranasally (local delivery) and intravenously (systemic administration). Pulmonary fibrosis was induced via a systemic subcutaneous infusion pump. We collected lung samples for RNA and protein analysis at various timepoints post AAV and bleomycin administration to determine optimal AAV transduction, efficacy, and ideal timing relative to the onset of fibrosis. These experiments aim to refine gene therapy conditions in our HPS1 mouse models, ultimately allowing us assess the potential of gene therapy as a viable treatment strategy for HPS1-PF.

Scientific Focus Area: Genetics and Genomics

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