Regulating neuroplasticity to restore upper limb and hand function after spinal cord injury
调节神经可塑性以恢复脊髓损伤后的上肢和手部功能
基本信息
- 批准号:MR/V002783/1
- 负责人:
- 金额:$ 92.52万
- 依托单位:
- 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:
- 关键词:
项目摘要
A spinal cord injury (SCI) can have devastating consequences, often resulting in a lifetime of disability and dependence. Most human SCIs occur in the neck (cervical) region and cause disability in the upper limbs and hands. Losing the ability to reach, grip, hold and pick up objects can severely limit independence, quality of life, participation in society and sense of self. There is currently no cure for SCI and no adequate therapies, therefore new regenerative therapies are urgently needed, particularly those that enable recovery of hand function.The enzyme therapy chondroitinase is a promising experimental treatment that enables new growth and connectivity (termed "neuroplasticity") by breaking down growth-blocking molecules in SCI scar tissue. There is now overwhelming pre-clinical evidence that treatment with chondroitinase enables recovery of lost function after SCI, demonstrated by numerous laboratories and in multiple species, including mouse, rat, cat, canine and primate. Chondroitinase is therefore a leading candidate for clinical development. The Bradbury lab and their collaborators have made many advances in optimizing and evaluating this therapy as a potential treatment option for SCI, recently developing an advanced gene therapy approach where a single injection of a viral vector containing a humanized version of the chondroitinase gene enables cells of the spinal cord to produce the enzyme directly into the injured tissue. In a further advance, the gene therapy has been engineered to contain an on/off switch which can be controlled by antibiotic administration (taking the antibiotic orally switches the gene on, and withdrawal switches the gene off), adding an important safety element plus a tool to examine when, and for how long, to turn the gene on to maximise the potential for recovery. With this approach we recently demonstrated recovery of reach and grasp ability in rats with cervical level contusion injuries when they were treated for 8 weeks with the gene continuously on. This exciting data, plus a recent study from our collaborator showing improved hand dexterity with chondroitinase gene therapy in hemi-contused monkeys, provides compelling evidence for testing this therapy in humans, and we are preparing for a first in man study. However, in order to improve the chances of clinical success, we first need to answer critical questions that remain: is recovery maintained after gene switch off? What are the long-term effects of gene therapy? How can we optimally apply this therapy with rehabilitative training to maximise the potential for recovery? Can we enable neuroplasticity and recover hand function in long term (chronic) SCI? What motor pathways are responsible for the recovery and are the targets for chondroitinase the same in rats and higher species? To address these, we will use rat cervical contusion injuries to mimic the most common type of human SCI; we will focus on recovery of hand function since this is the highest rated patient priority for improving independence and quality of life; we will apply targeted training to maximise the potential for recovery and for clinical relevance, since any new therapy for SCI will be applied alongside rehabilitative training in the clinic; we will apply this treatment to chronic SCI, to evaluate its potential application for the majority of patients who are living with long-established injuries. Finally, we will use gene silencing to determine the motor pathways that mediate recovery of hand function and we will carry out a cross-species tissue analysis comparison (rat, primate, human) to determine the optimal pattern of treatment for application in man. This project will provide essential information required to translate a promising regenerative therapy into a clinical treatment for restoring hand function in man and has the potential to improve the lives of millions of patients living with lifelong disability as a result of SCI.
脊髓损伤(SCI)可能会产生毁灭性的后果,通常会导致终身残疾和依赖。大多数人类SCI发生在颈部(颈部)区域,并导致上肢和手部残疾。失去接触、抓握、握住和拿起物体的能力会严重限制独立性、生活质量、社会参与和自我意识。目前SCI还没有治愈的方法,因此迫切需要新的再生疗法,特别是那些能够恢复手功能的疗法。酶疗法软骨素酶是一种很有前途的实验性治疗方法,通过打破SCI疤痕组织中的生长阻滞分子,使新的生长和连接(称为“神经可塑性”)成为可能。现在有压倒性的临床前证据表明,用软骨素酶治疗可以恢复SCI后失去的功能,这已在许多实验室和多个物种中得到证实,包括小鼠、大鼠、猫、犬和灵长类动物。因此,软骨素酶是临床开发的主要候选物。布拉德伯里实验室及其合作者在优化和评估这种疗法作为SCI的潜在治疗选择方面取得了许多进展,最近开发了一种先进的基因治疗方法,其中单次注射含有软骨素酶基因的人源化版本的病毒载体使脊髓细胞能够直接向受伤组织中产生酶。在进一步的进展中,基因治疗已经被设计成包含一个可以通过抗生素给药控制的开/关开关(口服抗生素会打开基因,而停药会关闭基因),增加了一个重要的安全因素和一个工具来检查何时以及多长时间打开基因,以最大限度地提高恢复的潜力。通过这种方法,我们最近证明了在颈部挫伤的大鼠中,当他们连续接受基因治疗8周时,达到和抓握能力的恢复。这一令人兴奋的数据,加上我们的合作者最近的一项研究显示,在半挫伤的猴子中,软骨素酶基因治疗改善了手的灵活性,为在人类中测试这种疗法提供了令人信服的证据,我们正准备进行首次人体研究然而,为了提高临床成功的机会,我们首先需要回答仍然存在的关键问题:基因关闭后恢复是否得以维持?基因治疗的长期效果是什么?我们如何最佳地应用这种疗法与康复训练,以最大限度地提高恢复的潜力?我们能否在长期(慢性)SCI中启用神经可塑性并恢复手部功能?什么样的运动途径负责恢复,软骨素酶的靶点在大鼠和高等动物中是否相同?为了解决这些问题,我们将使用大鼠颈部挫伤来模拟最常见的人类SCI类型;我们将专注于手功能的恢复,因为这是患者提高独立性和生活质量的最高优先级;我们将应用有针对性的培训,以最大限度地提高恢复和临床相关性的潜力,因为任何新的SCI治疗方法都将与康复训练一起应用于临床;我们将把这种疗法应用于慢性SCI,以评估它对大多数长期受伤的患者的潜在应用。最后,我们将使用基因沉默来确定介导手功能恢复的运动通路,并进行跨物种组织分析比较。(大鼠,灵长类动物,人的)以确定最佳的治疗模式应用于人类。该项目将提供必要的信息,将一个有前途的再生疗法转化为临床治疗,恢复手的功能,并有可能改善数百万因SCI而终身残疾的患者的生活。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Peripherally delivered Adeno-associated viral vectors for spinal cord injury repair
- DOI:10.1016/j.expneurol.2021.113945
- 发表时间:2021-12
- 期刊:
- 影响因子:5.3
- 作者:Jared D Sydney-Smith;A. B. Spejo;P. Warren;L. Moon
- 通讯作者:Jared D Sydney-Smith;A. B. Spejo;P. Warren;L. Moon
Enrichment of human embryonic stem cell-derived V3 interneurons using an Nkx2-2 gene-specific reporter.
- DOI:10.1038/s41598-023-29165-z
- 发表时间:2023-02-03
- 期刊:
- 影响因子:4.6
- 作者:
- 通讯作者:
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Elizabeth Bradbury其他文献
Creating the conditions for integrated systems of care: Learning from two large-scale approaches to changing thinking, practice and behaviour in Scotland and North West England
为综合护理系统创造条件:从苏格兰和英格兰西北部改变思维、实践和行为的两种大规模方法中学习
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Heather M. Shearer;Elizabeth Bradbury;June Wylie - 通讯作者:
June Wylie
Elizabeth Bradbury的其他文献
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{{ truncateString('Elizabeth Bradbury', 18)}}的其他基金
Technology-driven combinatorial therapy to rewire the spinal cord after injury (ReWire)
技术驱动的组合疗法可在损伤后重新连接脊髓 (ReWire)
- 批准号:
EP/X031497/1 - 财政年份:2023
- 资助金额:
$ 92.52万 - 项目类别:
Research Grant
Pharmacological inhibition or genetic deletion of a neurotoxin found abundantly at sites of spinal cord injury will neuroprotect and improve outcome.
对脊髓损伤部位大量发现的神经毒素进行药理学抑制或基因删除将起到神经保护作用并改善预后。
- 批准号:
MR/X003752/1 - 财政年份:2023
- 资助金额:
$ 92.52万 - 项目类别:
Research Grant
Identification of novel bioactive mediators of tissue scarring, inflammation and extracellular matrix remodeling after spinal cord injury
脊髓损伤后组织疤痕、炎症和细胞外基质重塑的新型生物活性介质的鉴定
- 批准号:
MR/R005532/1 - 财政年份:2017
- 资助金额:
$ 92.52万 - 项目类别:
Research Grant
The role of neuregulin-1 signalling in modulating repair and functional recovery following spinal cord injury
神经调节蛋白-1信号传导在调节脊髓损伤后修复和功能恢复中的作用
- 批准号:
MR/P012418/1 - 财政年份:2017
- 资助金额:
$ 92.52万 - 项目类别:
Research Grant
Acute and chronic spinal cord injury: novel studies of synaptogenesis, plasticity and mechanisms of repair
急性和慢性脊髓损伤:突触发生、可塑性和修复机制的新研究
- 批准号:
G1002055/1 - 财政年份:2011
- 资助金额:
$ 92.52万 - 项目类别:
Fellowship
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