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Cell therapy for Huntington's disease: addressing critical knowledge gaps

亨廷顿病的细胞疗法：解决关键的知识差距

基本信息

批准号：
MR/T033428/1
负责人：
Anne Elizabeth Rosser
金额：
$ 254.39万
依托单位：
CARDIFF UNIVERSITY
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT033428%2F1
关键词：
Cell therapy Huntington disease addressing

项目摘要

Cell therapies aim to replace cells that have been lost or damaged through disease, by transplanting cells into the area of loss. Such potential therapies are under consideration for a range of diseases of the brain, such as Parkinson's (PD) and Huntington's (HD) diseases. We are particularly interested in cell therapy for HD, a currently untreatable condition that is passed down through families and leads to progressive movement, thinking, and psychiatric deterioration, typically between the ages of 30-50. After transplantation into the brain, donor cells can survive and send out cellular processes to connect with particular areas of the host brain cells (their 'target' areas). We are particularly interested in cell transplantation for HD as the transplanted donor cells are placed directly into the area of cell loss and so have the opportunity to restore normal connections with the host brain. This is in contrast to conditions such as PD in which the donor cells have to be transplanted into their target regions (rather than the area of loss) and so the connections they make can never be completely normal. Thus, as well as being an area of unmet need, HD is a good 'model' in which to test whether transplanted cells can indeed restore normal connections in the brain. One of the primary changes seen in the brains of people with HD is death of a specific type of cell, called the medium spiny neuron (MSNs). Our goal is to "repair the brain" by replacing degenerated MSNs. We have shown in animal models and in early clinical trials that transplanting new MSNs into the brain results in cell grafts that survive and improve behavioural symptoms. However, the original cell source studied is very scarce and difficult to access, so it is essential to generate MSNs from new donor cell sources to allow for more widespread clinical application. We, and others, have identified stem cells as an optimal source of cells for this purpose and, over the last few years, have developed robust and promising methods to make functional MSNs from stem cells.In this project, our goal is to test these new stem cell-derived MSNs in rodents with HD. The aim is to determine whether the stem cell-derived MSNs transplants improve the same range of movement, thinking, and other behaviours that we see with transplants of the original cell source. We will use different rat models of HD to determine how robust the improvements are and which symptoms are improved, and we will compare these new stem cell-derived MSNs directly to the original 'authentic' cells that we have used in other studies. We also want to know how the cells improve these behaviours, and have a number of tools that will allow us to look at the whether the transplanted cells make direct physical contact with the host cells, whether they are electrically connected to host cells, and whether functional improvements disappear when we use special tools to temporarily switch off the grafts. We will also collect detailed molecular data that will allow us to thoroughly characterise the donor cells and grafts, and so provide the opportunity to further improve the cell therapy in the future. The information gathered in this application will be essential for us to move cell therapy for HD forward towards clinical application in a way that will be safe and continues to provide for therapeutic improvements.

细胞疗法的目标是通过将细胞移植到丢失的区域来取代因疾病而丢失或损坏的细胞。这种潜在的治疗方法正在考虑用于一系列脑部疾病，如帕金森氏病(PD)和亨廷顿病(HD)。我们对HD的细胞疗法特别感兴趣，这是一种目前无法治疗的疾病，通过家庭遗传，导致进行性运动、思维和精神恶化，通常在30-50岁之间。在移植到大脑后，供体细胞可以存活并发出细胞过程，与宿主脑细胞的特定区域(它们的“靶区”)连接。我们对HD的细胞移植特别感兴趣，因为移植的供体细胞被直接放置到细胞丢失的区域，因此有机会恢复与宿主大脑的正常连接。这与帕金森病等情况形成了鲜明对比，在帕金森氏症中，供体细胞必须被移植到他们的目标区域(而不是丢失的区域)，因此他们建立的连接永远不可能完全正常。因此，HD不仅是一个未得到满足的需求领域，也是测试移植细胞是否真的能恢复大脑中正常连接的一个很好的“模型”。HD患者大脑的主要变化之一是一种特殊类型的细胞死亡，这种细胞被称为中棘神经元(MSN)。我们的目标是通过替换退化的MSN来“修复大脑”。我们已经在动物模型和早期临床试验中表明，将新的MSN移植到大脑中会导致细胞移植存活并改善行为症状。然而，所研究的原始细胞来源非常稀缺且难以获得，因此从新的供体细胞来源产生MSN是必要的，以便更广泛地应用于临床。我们和其他人已经确定干细胞是实现这一目的的最佳细胞来源，在过去的几年里，我们已经开发出了强大而有前景的方法来从干细胞中制造出具有功能的MSN。在这个项目中，我们的目标是在患有HD的啮齿动物身上测试这些新的干细胞来源的MSN。目的是确定干细胞来源的MSN移植是否改善了我们在移植原始细胞来源时看到的相同范围的运动、思维和其他行为。我们将使用不同的HD大鼠模型来确定改善的力度有多大，哪些症状得到改善，并将这些新的干细胞来源的MSN直接与我们在其他研究中使用的原始“真实”细胞进行比较。我们还想知道细胞如何改善这些行为，并拥有许多工具，使我们能够观察移植细胞是否与宿主细胞有直接的物理接触，它们是否与宿主细胞电连接，以及当我们使用特殊工具暂时关闭移植物时，功能改善是否消失。我们还将收集详细的分子数据，使我们能够彻底确定供体细胞和移植物的特征，从而为未来进一步改进细胞治疗提供机会。在这项申请中收集的信息对于我们以一种安全的方式将HD的细胞疗法推向临床应用将是至关重要的，并继续提供治疗改进。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease.

DOI：
10.1016/j.jcyt.2020.06.001
发表时间：
2021-03
期刊：
Cytotherapy
影响因子：
4.5
作者：
Choompoo N;Bartley OJM;Precious SV;Vinh NN;Schnell C;Garcia A;Roberton VH;Williams NM;Kemp PJ;Kelly CM;Rosser AE
通讯作者：
Rosser AE

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward.

DOI：
10.1002/stem.3300
发表时间：
2021-02
期刊：
STEM CELLS
影响因子：
5.2
作者：
Bachoud-Levi, Anne-Catherine;Massart, Renaud;Rosser, Anne
通讯作者：
Rosser, Anne

Cognitive decline in Huntington's disease in the Digitalized Arithmetic Task (DAT).

DOI：
10.1371/journal.pone.0253064
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Lunven M;Hamet Bagnou J;Youssov K;Gabadinho A;Fliss R;Montillot J;Audureau E;Bapst B;Morgado G;Reilmann R;Schubert R;Busse M;Craufurd D;Massart R;Rosser A;Bachoud-Lévi AC
通讯作者：
Bachoud-Lévi AC

Defining the unknowns for cell therapies in Parkinson's disease.

定义帕金森氏病细胞疗法的未知数。