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Endobronchial Aerosolized AAV1.SERCA2a Gene Therapy in a Pulmonary Hypertension Pig Model: Addressing the Lung Delivery Bottleneck. | LitMetric

AI Article Synopsis

  • New therapies for pulmonary hypertension (PH) are lacking, but adeno-associated viral (AAV) gene therapy shows promise for treating the condition.
  • This study aimed to evaluate the effectiveness of endobronchial aerosolization for delivering AAV1 gene therapy in a pig model of PH and to find the best airway administration method.
  • Results indicated that endobronchial aerosolization led to greater viral uptake and improvements in PH symptoms compared to intratracheal delivery, making it a strong candidate for clinical applications.

Article Abstract

A disappointing number of new therapies for pulmonary hypertension (PH) have been successfully translated to the clinic. Adeno-associated viral (AAV) gene therapy has the potential to treat the underlying pathology of PH, but the challenge remains in efficient and safe delivery. The aims of this study were (1) to test the efficacy of endobronchial aerosolization delivery for AAV1-mediated sarcoplasmic/endoplasmic reticulum Ca ATPase 2a () gene therapy in a PH pig model and (2) to identify the most efficient airway administration modality for in-lung gene therapy in PH. We hypothesized that delivery to the distal bronchi increases lung viral uptake and avoids virus loss in off-target compartments. In part 1 of the study, PH was induced in pigs by surgically banding the pulmonary veins. Two months postsurgery, 1 × 10 viral genomes (vg) of AAV1. or saline was endobronchially aerosolized using a bronchoscope. Two months after aerosolization, high vg copies (vgc) were detected in the lungs, accompanied by functional and morphometrical amelioration of PH. In part 2 of the study, we directly compared the endobronchial aerosolization gene delivery to the intratracheal aerosolization in PH pigs. Endobronchial delivery demonstrated higher viral expression (6,719 ± 927 vs. 1,444 ± 402 vgc/100 ng DNA,  = 0.0017), suggesting this delivery modality is a promising method for clinical AAV gene therapy for PH.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9142769PMC
http://dx.doi.org/10.1089/hum.2021.274DOI Listing

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