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：
Elizabeth Bradbury
金额：
$ 92.52万
依托单位：
King's College London
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%2FV002783%2F1
关键词：
Regulating neuroplasticity restore upper limb

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) 可能会造成毁灭性后果，常常导致终生残疾和依赖。大多数人类脊髓损伤发生在颈部，导致上肢和手部残疾。失去伸手、抓握、握住和拾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。目前尚无治愈 SCI 的方法，也没有足够的治疗方法，因此迫切需要新的再生疗法，特别是那些能够恢复手部功能的疗法。酶疗法软骨素酶是一种有前途的实验性治疗方法，可以实现新的生长和连接（称为“神经可塑性”）通过分解 SCI 疤痕组织中的生长阻断分子。现在有压倒性的临床前证据表明，软骨素酶治疗可以恢复 SCI 后失去的功能，这已被众多实验室和多个物种（包括小鼠、大鼠、猫、犬和灵长类动物）证实。因此，软骨素酶是临床开发的主要候选者。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，其中单次注射含有人源化软骨素酶基因的病毒载体可使细胞脊髓产生的酶直接进入受伤的组织。更进一步的是，基因疗法被设计成包含一个可以通过抗生素给药来控制的开关（口服抗生素会打开基因，停药会关闭基因），添加了一个重要的安全元素和用于检查何时以及多长时间开启基因以最大限度地发挥恢复潜力的工具。通过这种方法，我们最近证明，当连续开启该基因治疗 8 周时，颈椎挫伤的大鼠的触及和抓握能力得到恢复。这一令人兴奋的数据，再加上我们合作者最近的一项研究显示，软骨素酶基因疗法可以改善半挫伤猴子的手部灵活性，为在人体中测试这种疗法提供了令人信服的证据，我们正在为首次人体研究做准备。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：基因关闭后恢复还能维持吗？基因治疗的长期影响是什么？我们如何才能最佳地应用这种疗法与康复训练，以最大限度地发挥康复潜力？我们能否在长期（慢性）脊髓损伤中实现神经可塑性并恢复手部功能？哪些运动通路负责恢复？软骨素酶的目标在大鼠和高等物种中是否相同？为了解决这些问题，我们将使用大鼠颈椎挫伤来模拟最常见的人类 SCI 类型；我们将重点关注手部功能的恢复，因为这是提高患者独立性和生活质量的最高优先事项；我们将应用有针对性的培训，以最大限度地发挥康复潜力和临床相关性，因为任何新的 SCI 疗法都将与临床康复培训一起应用；我们将把这种治疗方法应用于慢性 SCI，以评估其对大多数患有长期损伤的患者的潜在应用。最后，我们将利用基因沉默来确定介导手部功能恢复的运动途径，并将进行跨物种组织分析比较（大鼠、灵长类动物、人类）以确定适用于人类的最佳治疗模式。该项目将提供将有前途的再生疗法转化为恢复人类手部功能的临床治疗所需的基本信息，并有可能改善数百万因 SCI 导致终身残疾的患者的生活。