Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, P.O. Box 1030, New York, NY, 10029-6574, USA.
Department of Pediatric Cardiac Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Respir Res. 2023 Aug 11;24(1):197. doi: 10.1186/s12931-023-02487-2.
Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PH model.
A model of PH was established by the combination of left pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery.
Hemodynamic assessment 4 weeks after PH model the development demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p < 0.001), which was consistent with the definition of PH. We documented a significant increase in pulmonary vascular resistance in the saline-treated (6.79 ± 0.85 mm Hg) and empty capsid (6.94 ± 0.47 mm Hg) groups, but not in animals receiving Anc80L65.AC (4.44 ± 0.71 mm Hg, p < 0.001). Morphometric analysis demonstrated an increase in medial wall thickness in control groups in comparison to those treated with acid ceramidase. After acid ceramidase gene delivery, a significant decrease of pro-inflammatory factors, interleukins, and senescence markers was observed.
Gene delivery of acid ceramidase provided tropism to pulmonary tissue and ameliorated vascular remodeling with right ventricular dysfunction in pulmonary hypertension.
在肺动脉高压（PH）中，神经酰胺的上调导致鞘脂代谢稳态的紊乱，并使细胞向衰老状态转变。我们评估了酸神经酰胺酶基因转移在啮齿动物 PH 模型中的安全性、可行性和效率。
通过左肺切除术和苏根毒素注射建立 PH 模型。磁共振成像和右心导管检查证实 PH 的发展。动物接受经气管内给予携带酸神经酰胺酶（Anc80L65.AC）的合成腺相关病毒载体（Anc80L65）、空衣壳载体或生理盐水。基因传递后 8 周评估治疗效果。
PH 模型发展后 4 周的血流动力学评估显示，平均肺动脉压升高至 30.4±2.13mmHg，而假手术组为 10.4±1.65mmHg（p<0.001），符合 PH 的定义。我们记录到盐水处理组（6.79±0.85mmHg）和空衣壳组（6.94±0.47mmHg）的肺血管阻力显著增加，但接受 Anc80L65.AC 的动物没有增加（4.44±0.71mmHg，p<0.001）。形态计量分析显示，与接受酸神经酰胺酶治疗的动物相比，对照组的中膜厚度增加。酸神经酰胺酶基因传递后，促炎因子、白细胞介素和衰老标志物的水平显著降低。
酸神经酰胺酶的基因传递对肺组织具有亲嗜性，并改善了肺动脉高压中右心室功能障碍的血管重塑。
