Intratracheal SERCA2a Gene Therapy Interrupts the Formation of Plexiform Lesions and Rescues from Heart Failure in Severe Pulmonary Arterial Hypertension

Abstract

Introduction Drugs fail to improve long term outcomes in pulmonary hypertension (PAH), especially survival in end stages. Severe PAH presents with deadly high pulmonary vascular resistance [PVR] due to the progression of irreversible plexiform lesions [PLX], resulting in heart failure [HF]. SERCA2a [S2A], a calcium handling protein, has been shown effective in PAH via reprogramming endothelial and vascular smooth muscle cells via improving pulmonary flow and disrupting neointimal proliferation. Preliminary S2A studies have shown efficacy in reducing mean PA pressure [mPAP], however in less severe PAH models without HF or PLX. Here, we used a severe surgical PAH HF model and evaluated S2A gene therapy. Hypothesis S2A gene therapy will reduce PVR and rescue from HF via reducing the degree of PLX. Methods Twenty rats were divided between control or treatment groups, n=10 ea. All rats were induced with severe PAH via left pneumonectomy combined with Sugen (25mg/kg). Grade 4 maximum plexiform lesions develop with mPAP >35 mmHg @ 3 weeks. AAV1.S2A was administered via intratracheal aerosol at 2.5 × 1012 VGC after 3 weeks. MRI was performed at baseline, 3 and 6 weeks terminal with invasive mPAP. Harvest assays performed: QPCR of AAV1.S2A genome copies, S2A expression, and PLX pathology. Results S2A rats survived at 80% compared to control 50%. QPCR detection was very high in 5 S2A animals [1314±858 GC/cell], remaining 3 with average 2.5 fold in pulmonary smooth muscle anatomy 1B. Unlike control, which presented with higher frequency Grade 4 PLX 1C, the majority of S2A specimens had Grade 1-3 with less occurrence of PLX 1D. Conclusion S2A gene therapy is effective in reducing the progression of PLX. Gene therapy may serve as an adjunctive option for severe PAH patients.