Blocking chemotherapy-induced peripheral neuropathy by preserving axons

轴突是一种长“线”，它将电信号从一个神经细胞(神经元)传导到另一个神经细胞(神经元)，或者将信号从感觉器官或肌肉传递到肌肉。它们的极端长度(长达一米)使它们容易受到许多压力，包括遗传性疾病、毒素、炎症、病毒和身体损伤。这会导致多发性硬化症、糖尿病神经病变、运动神经元病和青光眼等疾病。在小鼠中，在了解如何预防或至少延缓轴突变性以应对许多这些压力方面取得了重大进展，我们小组在这项工作中发挥了重要作用。然而，到目前为止，还不清楚如何将其翻译成应用于患者。其中一个问题是轴突面临的许多压力是长期的和/或不可预测的。对轴突的长期保护，或在不可预见的时间保护，总是比在已知时间保护它们几天或几周更具挑战性。符合后一种模式的一个重要疾病是化疗引起的周围神经病变(CIPN)。CIPN是许多抗癌药物的剂量限制副作用，会引起强烈的疼痛。大多数接受这些癌症治疗的人都患有癌症，大约一半的幸存者在癌症治疗后继续遭受痛苦，其中许多人会度过余生。反复发生的刺痛、灼热或刺痛感或麻木，特别是手部和脚部的麻木，经常会扰乱睡眠，并大大降低生活质量。重要的是，尽管这一问题具有长期性，但它源于导致轴突退化的非常短期和可预测的治疗方案。CIPN是一种很好的预防性治疗候选药物。这个项目包括三个部分。首先，我们将建立在来自小鼠和细胞培养研究的令人鼓舞的数据的基础上，这些数据表明我们研究了多年的一种蛋白质在CIPN模型中保护轴突。我们将扩展之前的研究，测试它是否可以保护轴突免受更广泛的化疗药物的损害，是否无限期地保护它们，以及它是否除了阻止轴突退化之外还可以减轻疼痛。其次，我们最近发现了一种通过模仿保护性基因的作用来保护轴突的药物，因此我们将在CIPN动物模型中测试这种药物是否保护轴突并防止症状。重要的是，这种药物已经在人类身上使用(实际上是在癌症的临床试验中)，所以如果在这里成功，确定它是否在人类体内保留轴突的测试可能会很快进行。第三，我们的目标是更多地了解导致CIPN的轴突变性的机制。特别是，我们专注于沿神经的必要蛋白质和细胞器的运输，称为轴突运输，这一过程已知被一些抗癌药物破坏。我们会问，这对几种诱导CIPN的药物是否普遍，运输是以什么方式中断的，以及导致轴突变性的直接后果是什么，这是我们在该领域的专业知识应该确保良好进展的一个领域。这将有助于我们开发进一步的策略来保护CIPN中的轴突。这个项目的成功对于预防癌症治疗可能导致的神经并发症将是重要的。然而，它也应该是重要的，以表明我们可能如何解决其他主要的轴突障碍。糖尿病神经病变就是一个很好的例子，它与CIPN有许多共同的症状，在英国影响着100多万人。多发性硬化症将是另一个例子，在炎症性复发期间轴突也会受到暂时的压力。到目前为止，还没有针对任何轴突疾病的预防性治疗方法。通过专注于一种具有相对简单的机制、良好的动物模型和非常现实的开发治疗可能性的疾病，应该有可能取得重大进展，为其他重要的轴突疾病提供重要的线索。

Axons are long 'wires' that conduct electrical signals from one nerve cell (neuron) to another, or convey signals from sense organs or to muscles. Their extreme length (up to one meter) makes them vulnerable to many stresses, including inherited disorders, toxins, inflammation, viruses and physical injury. This results in disorders such as multiple sclerosis, diabetic neuropathy, motor neuron disease and glaucoma. Significant progress has been made in mice in understanding how axon degeneration can be prevented, or at least delayed, in response to many of these stresses and our group has played a prominent role in this work. However, until now it has not been clear how this could be translated for application in patients. One of the problems is that many of the stresses axons face are chronic and/or unpredictable. Long-term protection of axons, or protection at an unforeseen time, will always be more challenging that protecting them for a few days or weeks at a known time. One important disorder that fits this latter pattern is chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a dose-limiting side effect of many cancer drugs, causing intense pain. Most recipients of these cancer treatments suffer from it and around half of survivors continue to suffer afterwards, many for the rest of their lives. Recurrent stabbing, burning or tingling sensations, or numbness, particularly in hands and feet, regularly disrupt sleep and greatly reduce quality of life. Importantly, despite the long-term nature of the problem it stems from a very short and predictable treatment regime that causes axon degeneration. CIPN is an excellent candidate for preventative therapy. This project has three parts. First, we will build on encouraging data from mouse and cell culture studies indicating that a protein we have studied for many years protects axons in CIPN models. We will extend the previous studies by testing whether it preserves axons from damage by a wider range of chemotherapy drugs, whether it protects them indefinitely and whether it reduces the pain in addition to blocking axon degeneration. Second, we recently identified a drug that preserves axons by mimicking an effect of the protective gene, so we will test whether this drug preserves axons and prevents symptoms in CIPN animal models. Importantly, this drug is already in use in man (in clinical trials for cancer in fact) so if successful here, tests to determine whether it preserves axons in man could proceed quickly. Third, we aim to find out more about the mechanism that underlies the axon degeneration leading to CIPN. In particular, we focus on the transport of essential proteins and organelles along nerves, termed axonal transport, a process known to be disrupted by some cancer drugs. We will ask whether this is common to several drugs that induce CIPN, in what way is the transport disrupted, and what are the immediate consequences that lead to axon degeneration, an area in which our expertise in this field should ensure good progress. This will help us to develop further strategies to preserve axons in CIPN.Success in this project would be important for preventing the neurological complications that can result from cancer therapy. However, it should also be important in indicating how we might tackle other major axonal disorders. Diabetic neuropathy, which shares many symptoms with CIPN and affects over 1 million people in the UK, would be one excellent example. Multiple sclerosis, in which axons also come under temporary stress during inflammatory relapses, would be another. Until now there are no preventative therapies for any axonal disorders. By focusing on a disorder with a relatively straightforward mechanism, good animal models, and a very realistic likelihood of developing a therapy, it should be possible to make significant progress that provides important leads also for other important axonal diseases.