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

Background

Snakebite 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 research

For 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 perform
cutting-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 project

Here, 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/impact

From 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.

Snakebite-induced muscle damage is primarily caused by venom metalloproteases and cytotoxic phospholipase A2s (commonly from viper venoms). The currently used antivenoms are ineffective in treating/preventing this condition due to larger IgG molecules and blocked/damaged capillaries along with fibrosis in affected muscle. Hence, surgical procedures are used to perform fasciotomy and debridement, and in severe cases, amputation to remove the affected limb. We developed a unique venom-induced muscle damage (VIMD) model in mice and characterised the severity of damage and established the key underlying molecular mechanisms behind this condition. We determined that the persistent actions of venom toxins continue to damage distinct muscle components and prevent muscle regeneration. We hypothesise that it is possible to induce muscle regeneration during VIMD as all the regeneration phases are active. Hence, we propose to develop combinational therapeutic strategies using regenerative medicine and next generation antivenoms to prevent/treat VIMD. We will determine the impact of orally bioavailable drugs such as marimastat and varespladib along with toxin-specific human single chain/domain monoclonal antibodies to neutralise the actions of venom metalloproteases and phospholipase A2 during VIMD using Russell's viper venom and isolated toxins such as a metalloprotease and phospholipase A2. Similarly, regenerative medicine using secretome of adipose-derived mesenchymal stem cells and releasate from human activated platelets will be used to determine their regenerative capability following VIMD. Based on these results, specific combinational therapeutic approaches will be developed and investigated in VIMD under diverse settings. Overall, this study, for the first time, will develop robust combinational treatment strategies that can be further analysed in pre-clinical and clinical studies to treat/prevent snakebite-induced muscle damage and subsequent permanent disabilities.