Development of a Gal-free Calcification Resistant Porcine Pericardial Heart Valve

无加仑抗钙化猪心包心脏瓣膜的研制

• 批准号: MC_PC_21007
• 负责人: Christopher Mcgregor
• 金额: $ 8.59万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_PC_21007
• 关键词: Development; Gal; free; Calcification; Resistant

Heart valves control the normal flow of blood through the lungs and body. These valves may be damaged because of birth defects, old age, or infection. This damage may require heart valves to be replaced with artificial valves to improve the quality of life of heart valve disease patients or to save their lives. There are about 300,000 heart valve replacements worldwide each year. Replacement valves are either mechanical, made of carbon and metal, or biological, made of non-living tissue generally obtained from pigs or cows. Patients and doctors tend to prefer biological heart valves (BHVs) because they generally do not require blood thinners, which are needed with mechanical valves. In younger patients (<60 years) and in children, BHVs wear out more rapidly, sometimes within 5 years. BHVs fail because they build up bone-like deposits of calcium, which weaken the valve, leading to tears, or obstructed blood flow as the calcium deposits block the opening of the valve. Scientists and commercial valve companies have long sought to produce BHVs, which do not calcify, because these could be used in younger patients without the need for blood thinners. So far, calcification-blocking treatments have been able to reduce valve calcification when tested in animals, but have not been able stop calcification in patients or reliably allow the use of BHVs in younger adults. We identified a type of rejection that makes calcification worse in BHV material. This rejection is unique to humans as the human immune system reacts with a substance, called Gal present on BHVs. To block this rejection reaction we have genetically altered pigs that can be used to make BHVs called Gal knockout pigs. The Gal knockout pigs are healthy and normal and their Gal-free tissue has reduced calcification. Before using Gal knockout tissue in patients, we need to be certain the genetic change in Gal knockout pigs has not had a damaging effect on the tissues used to make these BHVs. We have compared the tissues in current standard and Gal knockout BHVs and used simple tests, such as measuring how hard it is to stretch and tear the tissue, to see if the mechanical properties of Gal knockout tissue remain strong and unchanged. We have also made BHVs using both current standard and Gal knockout tissue, and tested them in a laboratory machine that mimics their function in the heart. Both types of BHVs performed similarly in these tests. This current project is to compare how well the Gal knockout tissue works as a BHV in the standard industry animal model. This test is the only way of determining if the valve works well inside of the body and can function to control the normal flow of blood in the heart. Successfully performing this test, which is required by International standards, is a major step forward to making a new BHV, which reduces calcification and be usable in younger patients. Such a new BHV would greatly increase the quality of life for patients. If successful, we hope to advance a new Gal knockout heart valve for a clinical test in man.

心脏瓣膜控制肺部和身体的正常血液流动。这些瓣膜可能因出生缺陷、年老或感染而受损。这种损害可能需要用人工瓣膜代替心脏瓣膜，以改善心脏瓣膜病患者的生活质量或挽救他们的生命。全世界每年约有30万例心脏瓣膜置换手术。替代阀门要么是机械的，由碳和金属制成，要么是生物的，由通常从猪或牛身上获得的非活体组织制成。患者和医生倾向于选择生物心脏瓣膜（bhv），因为它们通常不需要血液稀释剂，而机械瓣膜需要血液稀释剂。在年轻患者（<60岁）和儿童中，bhv磨损更快，有时在5年内。bhv的失败是因为它们会形成骨样的钙沉积，这会削弱瓣膜，导致撕裂，或者由于钙沉积阻塞了瓣膜的开口而阻碍了血液流动。科学家和商业瓣膜公司长期以来一直在寻求生产不会钙化的bhv，因为这些bhv可以在不需要血液稀释剂的情况下用于年轻患者。到目前为止，在动物试验中，钙化阻断治疗已经能够减少瓣膜钙化，但还不能阻止患者的钙化，也不能可靠地允许在年轻人中使用bhv。我们发现了一种使BHV材料钙化恶化的排斥反应。这种排斥反应是人类独有的，因为人类免疫系统会与bhv上的一种叫做Gal的物质发生反应。为了阻止这种排斥反应，我们对猪进行了基因改造，可以用来制造bhv，称为Gal敲除猪。敲除Gal的猪是健康和正常的，它们的无Gal组织减少了钙化。在对患者使用Gal敲除组织之前，我们需要确定Gal敲除猪的遗传变化不会对用于制造bhv的组织产生破坏性影响。我们比较了目前标准bhv和Gal敲除bhv中的组织，并使用简单的测试，例如测量拉伸和撕裂组织的难度，以观察Gal敲除组织的机械性能是否保持强大和不变。我们还使用当前标准组织和Gal敲除组织制造bhv，并在实验室机器中模拟它们在心脏中的功能进行测试。在这些测试中，两种bhv的表现相似。目前的项目是比较Gal敲除组织在标准工业动物模型中作为BHV的效果如何。这个测试是确定瓣膜在体内是否工作良好，是否能控制心脏正常血液流动的唯一方法。成功完成这项符合国际标准的测试，是制造新型BHV的重要一步，这种BHV可以减少钙化，并可用于年轻患者。这种新的BHV将大大提高患者的生活质量。如果成功，我们希望推进一种新的Gal基因敲除心脏瓣膜用于人体临床试验。