Development of a Gal-free Calcification Resistant Porcine Pericardial Heart Valve: Establishment of Biological Tissue Equivalence.

无加仑抗钙化猪心包心脏瓣膜的开发:生物组织等效性的建立。

基本信息

  • 批准号:
    MR/R006393/1
  • 负责人:
  • 金额:
    $ 173.14万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2018
  • 资助国家:
    英国
  • 起止时间:
    2018 至 无数据
  • 项目状态:
    已结题

项目摘要

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.
心脏瓣膜控制血液通过肺部和身体的正常流动。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替换心脏瓣膜,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术。置换瓣膜是由碳和金属制成的机械瓣膜,或由通常从猪或牛获得的非活体组织制成的生物瓣膜。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机械瓣膜所需的血液稀释剂。在年轻患者(<60岁)和儿童中,BHV磨损更快,有时在5年内。BHV失败是因为它们积累了骨样钙沉积物,这削弱了瓣膜,导致撕裂,或者由于钙沉积物阻塞了瓣膜的打开而阻碍了血流。长期以来,科学家和商业瓣膜公司一直在寻求生产不会钙化的BHV,因为这些BHV可以用于年轻患者,而不需要血液稀释剂。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。我们确定了一种排斥反应,使BHV材料的钙化更糟。这种排斥是人类独有的,因为人类免疫系统与BHV上存在的一种称为Gal的物质反应。为了阻止这种排斥反应,我们有转基因猪,可以用来制造BHV,称为Gal敲除猪。Gal敲除猪是健康和正常的,并且它们的无Gal组织具有减少的钙化。在将Gal敲除组织用于患者之前,我们需要确定Gal敲除猪的遗传变化对用于制造这些BHV的组织没有损害作用。我们比较了当前标准和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,以查看Gal敲除组织的机械性能是否保持坚固和不变。我们还使用目前的标准和Gal敲除组织制造了BHV,并在模拟其心脏功能的实验室机器中对其进行了测试。两种类型的BHV在这些测试中表现相似。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的工作情况。该测试是确定瓣膜是否在体内正常工作并能够控制心脏中血液正常流动的唯一方法。成功执行国际标准要求的这项测试是制造新的BHV的重要一步,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敲除心脏瓣膜用于人体临床试验。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biological Equivalence of GGTA-1 Glycosyltransferase Knockout and Standard Porcine Pericardial Tissue Using 90-Day Mitral Valve Implantation in Adolescent Sheep.
  • DOI:
    10.1007/s13239-021-00585-0
  • 发表时间:
    2022-06
  • 期刊:
  • 影响因子:
    1.8
  • 作者:
    McGregor, Christopher;Salmonsmith, Jacob;Burriesci, Gaetano;Byrne, Guerard
  • 通讯作者:
    Byrne, Guerard
B4GALNT2 and xenotransplantation
B4GALNT2 和异种移植
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Byrne G
  • 通讯作者:
    Byrne G
Does human leukocyte antigens sensitization matter for xenotransplantation?
  • DOI:
    10.1111/xen.12411
  • 发表时间:
    2018-05
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Byrne GW
  • 通讯作者:
    Byrne GW
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Christopher Mcgregor其他文献

Christopher Mcgregor的其他文献

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{{ truncateString('Christopher Mcgregor', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 173.14万
  • 项目类别:
    Intramural
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开发。
  • 批准号:
    MR/L013193/1
  • 财政年份:
    2014
  • 资助金额:
    $ 173.14万
  • 项目类别:
    Research Grant

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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
  • 财政年份:
    2021
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    $ 173.14万
  • 项目类别:
    Intramural
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