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

MICA：使用再生医学和下一代抗蛇毒血清的组合治疗方法来预防/治疗蛇咬伤引起的肌肉损伤

• 批准号: MR/W019353/1
• 负责人: Sakthivel Vaiyapuri
• 金额: $ 65.23万
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW019353%2F1
• 关键词: MICA; Combinational; therapeutic; approaches; using

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.

蛇咬伤是一种高度优先的被忽视的热带疾病，影响全世界超过500万人，导致约270万人中毒，140，000人死亡，特别是450，000人终身残疾。它主要影响生活在印度等发展中国家农村地区的贫穷农业社区。抗蛇毒血清是目前唯一可用的治疗蛇咬伤的药物。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咬伤部位的肌肉损伤方面无效，这通常会导致永久性残疾（由于肢体丧失）。临床医生目前使用外科手术切除受影响的肌肉或截肢受损的肢体。这些额外的外科手术大大增加了蛇咬伤受害者的治疗费用。因此，除了死亡之外，蛇咬伤造成的永久性残疾还对受害者及其家庭造成严重的社会经济影响。因此，迫切需要开发新的，有效的和更便宜的治疗策略，可以预防和治疗蛇咬伤引起的肌肉损伤和随后的永久性disability.Our以前的研究在过去的六年中，作为在英国研究毒液的少数几个小组之一，我们一直在调查蛇毒引起肌肉损伤的机制。我们开发了强大的工具，技能和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，以在这一领域进行尖端研究。从我们以前的研究中，我们发现受影响肌肉中关键毒液毒素的长期作用会导致持续的损伤和脂肪积累，从而阻止肌肉再生。因此，在蛇咬伤后，必须同时阻断毒液毒素并诱导肌肉生长。由于抗蛇毒血清在这种情况下没有用，我们认识到，（通过我们的初步数据）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。我们建议研究使用特定药物的意义，（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期间中和毒液毒素。同样，我们将建立再生医学方法（用于治疗/控制各种肌肉和骨骼疾病）在毒液损伤肌肉中诱导肌肉生长的影响。基于这些结果，我们将开发这些分子的特定组合，并确定它们同时中和毒液毒素并在毒液诱导的肌肉损伤后诱导肌肉生长的能力。这些数据将形成我们未来的临床研究的基础上，以评估在人类snakebite victims.Expected outcomes/impactFrom这个项目的肌肉损伤，我们的目标是制定具体的组合治疗策略，以预防和治疗蛇咬伤引起的肌肉损伤和随后的残疾。此外，我们将建立详细的分子和细胞机制，在动物模型中支持毒液诱导的肌肉损伤。这里开发的组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。总的来说，蛇咬伤引起的肌肉损伤是一种被忽视的热带疾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，以预防/治疗这一重大问题，它导致生活在农村地区的贫困社区的许多永久性残疾。通过重新利用现有的治疗蛇咬伤引起的肌肉损伤的方法，我们可以大大减少新药的发现和开发成本，以及大量的时间。这将大大减少发展中国家农村贫困人口的最终用户的治疗费用。

项目成果

An Unnecessary Russell's Viper Bite on the Tongue Due to Live Snake Worship and Dangerous First Aid Emphasise the Urgent Need for Stringent Policies.

• DOI: 10.3390/toxins14120817
• 发表时间: 2022-11-22
• 期刊: Toxins
• 影响因子: 4.2
• 作者: Senthilkumaran S;Arathisenthil SV;Williams J;Williams HF;Thirumalaikolundusubramanian P;Patel K;Vaiyapuri S
• 通讯作者: Vaiyapuri S

Differential effects of the venoms of Russell's viper and Indian cobra on human myoblasts

• DOI: 10.1038/s41598-024-53366-9
• 发表时间: 2024-02-07
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Bin Haidar，Husain;Almeida，Jose R.;Patel，Ketan
• 通讯作者: Patel，Ketan

First Insights into the Venom Composition of Two Ecuadorian Coral Snakes.

• DOI: 10.3390/ijms232314686
• 发表时间: 2022-11-24
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Hirata's disease (insulin autoimmune syndrome) following envenomation by a common krait.

被常见的金环蛇毒害后出现的平田氏病（胰岛素自身免疫综合征）。

• DOI: 10.1016/j.toxicon.2022.09.009
• 发表时间: 2022
• 期刊: official journal of the International Society on Toxinology
• 作者: Senthilkumaran S