MICA: Combinational therapeutic approaches using regenerative medicine and next generation antivenoms to prevent/treat snakebite-induced muscle damage

背景蛇咬伤是一种高度优先的被忽视的热带疾病，影响着全球500多万人，导致约270万人中毒，14万人死亡，特别是45万人永久残疾。它主要影响生活在印度等发展中国家农村地区的穷人和农业社区。抗蛇毒血清是目前唯一可用的治疗蛇咬伤的方法。虽然抗蛇毒血清有助于挽救生命，但它们在预防和治疗蛇咬伤引起的局部肌肉损伤方面效果不佳，这种损伤往往会导致永久性残疾(由于失去肢体)。临床医生目前使用外科手术来移除受影响的肌肉或截断受损的肢体。这些额外的外科手术大大增加了蛇咬伤受害者的治疗成本。因此，除了死亡外，蛇咬造成的永久性残疾还会对受害者及其家人造成严重的社会经济影响。因此，迫切需要开发新的、有效和廉价的治疗策略来预防和治疗蛇咬导致的肌肉损伤和随后的永久性残疾。我们之前的研究在过去的六年里，作为英国为数不多的研究蛇毒的小组之一，我们一直在研究蛇毒导致肌肉损伤的机制。我们开发了强大的工具、技能，并与研究毒液的领先科学家和治疗印度蛇咬伤受害者的临床医生合作，以执行该领域的尖端研究。从我们以前的研究中，我们发现关键毒素在受影响的肌肉中的长期作用会导致持续的损伤和脂肪的积累，从而阻止肌肉的再生。因此，在被蛇咬伤后，同时阻止毒素和诱导肌肉生长是至关重要的。由于抗蛇毒血清在这种情况下没有用处，我们(通过我们的初步数据)认识到使用特定的现有药物和再生医学方法来预防和治疗蛇咬伤引起的肌肉损伤。本项目的研究计划在这里，我们建议调查使用特定的药物(开发用于治疗其他人类疾病)和人类毒素特异性抗体在小鼠毒液诱导的肌肉损伤过程中中和毒素的意义。同样，我们将确定再生医学方法(用于治疗/控制各种肌肉和骨骼疾病)在诱导毒液受损肌肉中的肌肉生长方面的影响。基于这些结果，我们将开发这些分子的特定组合，并确定它们在毒液诱导的肌肉损伤后同时中和毒素和诱导肌肉生长的能力。这些数据将成为我们未来临床研究的基础，以描述人类蛇咬受害者的肌肉损伤。预期结果/影响从这个项目中，我们的目标是开发特定的组合治疗策略，以预防和治疗蛇咬导致的肌肉损伤和随后的残疾。此外，我们将在动物模型中建立支持毒液诱导的肌肉损伤的详细的分子和细胞机制。这里开发的联合治疗方法将为进一步的临床前和临床研究奠定坚实的基础。总体而言，蛇咬引起的肌肉损伤是一种被忽视的热带病的一个被忽视的方面，因此，通过这个项目，我们将开始一项新的倡议，开发创新的治疗方法来预防/治疗这一重大问题，这一问题在农村地区的贫困社区中造成许多永久性残疾。通过改变现有治疗毒蛇咬伤引起的肌肉损伤的方法，我们可以极大地减少新药的发现和开发成本，并显著缩短时间。这将大大降低生活在发展中国家的贫困农村人口的最终用户的治疗费用。

BackgroundSnakebite is a high priority neglected tropical disease that affects over 5 million people worldwide resulting in around 2.7 million envenomings, 140,000 deaths and notably, 450,000 permanent disabilities. It predominantly affects the poor, agricultural communities living in rural areas of developing countries such as India. Antivenoms are the only currently available treatment for snakebites. While the antivenoms help save lives, they are ineffective in preventing and treating snakebite-induced muscle damage at the local bite site which often results in permanent disabilities (due to loss of limbs). The clinicians currently use surgical procedures to remove the affected muscle or amputate the damaged limb. These additional surgical procedures substantially increase the treatment cost for snakebite victims. Therefore, in addition to deaths, the permanent disabilities caused by snakebites lead to severe socioeconomic impact on victims and their families. Hence, there is an urgent need to develop new, effective and cheaper treatment strategies that can prevent and treat snakebite-induced muscle damage and subsequent permanent disabilities.Our previous researchFor the last six years, as one of the very few groups researching on venoms in the UK, we have been investigating the mechanisms through which snake venoms induce muscle damage. We have developed robust tools, skills and collaborations with leading scientists who research venoms and clinicians who treat snakebite victims in India to performcutting-edge research in this area. From our previous research, we discovered that the prolonged actions of key venom toxins in the affected muscle induces continuous damage and accumulation of fat, and thereby prevent muscle regrowth. Hence, it is essential to simultaneously block the venom toxins and induce muscle growth following a snakebite. Since, the antivenoms are not useful in this scenario, we recognised (through our preliminary data) the use of specific existing drugs and regenerative medicine approaches to prevent and treat snakebite-induced muscle damage.Research plans for this projectHere, we propose to investigate the significance of using specific drugs (that were developed to treat other human diseases) and human toxin-specific antibodies in neutralising venom toxins during venom-induced muscle damage in mice. Similarly, we will establish the impact of regenerative medicine approaches (that are used to treat/control various muscle and bone diseases) in inducing muscle growth in venom damaged muscle. Based on these outcomes, we will then develop specific combinations of these molecules and determine their ability to simultaneously neutralise venom toxins and induce muscle growth following venom-induced damage in muscle. These data will form the basis for our future clinical studies to characterise the muscle damage in human snakebite victims.Expected outcomes/impactFrom this project, we aim to develop specific combinational treatment strategies to prevent and treat snakebite-induced muscle damage and subsequent disabilities. Moreover, we will establish detailed molecular and cellular mechanisms that underpin venom-induced muscle damage in animal models. The combinational treatment approaches developed here will form a strong basis for further pre-clinical and clinical studies. Overall, snakebite-induced muscle damage is a neglected aspect of a neglected tropical disease, and therefore, through this project, we will begin a new initiative to develop innovative treatments to prevent/treat this significant issue which causes numerous permanent disabilities among poor communities living in rural areas. By repurposing existing treatments for snakebite-induced muscle damage, we can hugely reduce the new drug discovery and development costs, and significant time. This will substantially reduce the treatment costs for end users who are poor rural populations living in developing countries.