Healthy longevity gene inspired therapy to rescue cardiovascular disease in progeria

Hutchinson-Gilford早衰症(HGPS)是一种由基因及相关蛋白异常引起的罕见疾病。由于缺乏有效的治疗方法，智力发育完全正常的HGPS儿童死于心血管疾病的平均年龄为~14岁。该项目提出了一种新的解决方案，包括转移在健康长寿个体中发现的有益基因，以挽救HGPS患者典型的心血管早衰。作为第一步，我们将在受HGPS影响的小鼠身上测试新疗法，然后提出在患者身上进行研究。我们的团队已经发现了一种有益的BPIFB4基因变体，它与非凡的长寿有关，更重要的是，它与一些百岁老人的持久健康有关。接下来，我们在动物模型中证明了BPIFB4基因的转移可以减轻心脏病发作、糖尿病和高血压的痛苦。此外，BPIFB4基因治疗减少了高龄小鼠的虚弱、动脉粥样硬化和心脏损伤。初步研究表明，长寿的BPIFB4突变可以使HGPS儿童功能障碍的某些分子机制受益。我们将确定BPIFB4基因治疗在HGPS小鼠中的疗效，观察其保护心脏和血管功能的治疗能力。此外，我们将利用HGPS患者的人体细胞来研究这种益处的基础机制。如果结果是阳性的，我们将继续我们的研究，确认其无毒性(该基因变异与改善人类健康相关的事实已经令人放心)，确定延长益处的最佳治疗剂量/时间，以及鉴于获得患者临床研究的许可，在现有药物中添加BPIFB4疗法的优势。

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by an abnormal gene and related protein. Due to the lack of an effective cure, children with HGPS, who have completely normal intellectual development, die of cardiovascular disease at the average age of ~14 years. This project proposes a new solution consisting of transferring a salutary gene that is found in healthy long-living individuals to rescue the premature cardiovascular senescence typical of HGPS patients. We will test the new treatment in mice affected by HGPS as an initial step before proposing a study in patients.Our team has discovered a beneficial variant of the BPIFB4 gene, which associates with exceptional longevity and, even more importantly, with long-lasting health in some centenarians. Next, we demonstrated that the transfer of the BPIFB4 gene attenuates the suffering from a heart attack, diabetes, high blood pressure in animal models. Moreover, BPIFB4 gene therapy reduced frailty, atherosclerosis, and heart damage in very old mice. Preliminary studies showed that the longevity BPIFB4 mutation can benefit some molecular mechanisms that are dysfunctional in HGPS children. We will determine the efficacy of BPIFB4 gene therapy in HGPS mice, looking at the treatment ability to preserve heart and blood vessel function. In addition, we will investigate the mechanisms underpinning the benefit, using human cells from HGPS patients.If results are positive, we will continue our research confirming the lack of toxicity (the fact that the gene variant is associated with improved human health is already reassuring), defining the best dose/timing of treatment for prolonged benefit, and the advantage of adding BPIFB4 therapy to current drugs in view of obtaining permission for a clinical study in patients.