Humboldt-Universität zu Berlin, Institute of Chemistry , Brook-Taylor-Str. 2, 12489 Berlin , Germany
Expert Opin Ther Pat. 2015 Jun;25(6):723-7. doi: 10.1517/13543776.2015.1025751. Epub 2015 Mar 18.
Pulmonary arterial hypertension (PAH) is a disease of various etiologies, characterized by progressive vascular remodeling that leads to right ventricular hypertrophy and heart failure. Although modern therapy improves life quality of patients, prognosis of PAH remains poor with a high mortality rate. Overexpression of microRNA (miR)-145, which was found in PAH patients, leads to progression of vascular remodeling. The current patent proposes a strategy using antisense oligonucleotides (ASOs) against miR-145 for prevention and treatment of PAH.
Overexpression of miR-145 was shown in chronic hypoxia mouse models and PAH patients. Genetic ablation of miR-145 in hypoxic mice led to improved hemodynamic and vascular remodeling parameters. Furthermore, miR-145 inhibition by ASOs has been performed in chronic hypoxia mouse models. The experiments showed improved systolic right ventricular pressure and a decreased percentage of vascular remodeling.
Although the mouse model does not display the full pathology of PAH, the inhibition of miR-145 by modified ASOs is promising for prevention and reversion of vascular remodeling. Whether such ASOs can be efficiently delivered and will prevent progression of PAH pathology and may lead to an extended lifespan of PAH patients remains to be elucidated.
肺动脉高压（PAH）是一种病因多样的疾病，其特征是进行性血管重构，导致右心室肥厚和心力衰竭。尽管现代疗法改善了患者的生活质量，但 PAH 的预后仍然很差，死亡率很高。在 PAH 患者中发现的 microRNA（miR）-145 的过表达导致血管重构的进展。本专利提出了一种使用针对 miR-145 的反义寡核苷酸（ASO）来预防和治疗 PAH 的策略。
miR-145 的过表达在慢性低氧小鼠模型和 PAH 患者中得到了证实。在低氧小鼠中敲除 miR-145 导致血流动力学和血管重构参数的改善。此外，在慢性低氧小鼠模型中已经进行了 miR-145 的 ASO 抑制实验。实验表明，收缩期右心室压力得到改善，血管重构的百分比降低。
尽管小鼠模型并未显示出 PAH 的全部病理学特征，但经过修饰的 ASO 对 miR-145 的抑制对于预防和逆转血管重构具有很大的潜力。这些 ASO 能否有效地递送至并预防 PAH 病理学的进展，以及是否可能延长 PAH 患者的寿命，仍有待阐明。
