Development of a humanised delivery system for interleukin 2 to treat traumatic brain injury
Lead Research Organisation:
University of Cambridge
Department Name: Pathology
Abstract
Traumatic brain injury is one of the leading neurological causes of disability in the world, with many patients developing long-lasting cognitive and mental deficits. The involvement of the immune system in the pathology of traumatic brain injury has clearly been established. Traumatic brain injury can be divided into two distinct stages: the initial trauma itself (e.g. blunt force trauma, blast injuries) and a secondary inflammation that develops afterwards. The initial trauma causes cell death in the brain at the impact site, releasing signals that drive an inflammatory response. This inflammation is similar to the bruising that occurs when an ankle or knee is twisted, with the difference being the swelling of the brain within the skull is much more toxic to the tissue, due to the pressure created. This inflammation following a traumatic brain injury causes a secondary wave of damage generation to the brain tissue, which can kill as many brain cells as the primary injury itself. This secondary wave can continue for months or even years, increasing the duration and severity of the brain damage. This proposal seeks to prevent and repair the inflammation-mediated damage caused during this second wave of traumatic brain injury.
Therapeutic strategies aimed at different parts of the immune system thus far failed, or were only partially successful, largely because of the inability of drugs to cross over the "blood-brain barrier". This barrier protects the brain from harmful toxins, but in the case of potentially beneficial drugs it also prevents those drugs from reaching the brain where they are needed. We have generated a new system for delivering anti-inflammatory agents to the brain, by using a "gene delivery" system that teaches brain cells to produce the anti-inflammatory drug that the need themselves, bypassing the blood-brain barrier. Our data demonstrates that we can increase the number of "regulatory T cells" in the brain of treated mice. These are anti-inflammatory white blood cells that actively reduce inflammation in the brain and promote repair. Using a mouse model of traumatic brain injury, this treatment reduced the damage following injury by 50%. As there are currently no drugs available that prevent traumatic brain injury patients from secondary brain damage, a new drug with 50% protective capacity would have enormous social and economic impact, reducing the long-term cognitive loss in patients, improving the quality of life of carers, family and friends, and reducing the economic burden of injury by preventing long-term disability that impedes the ability to work and live independently.
In this grant we are seeking to develop this therapeutic approach for commercialisation. The drug is currently optimised for use in mice, and requires optimisation of a humanised version. We also need to initiate the regulatory process for testing in humans and the production process to manufacture clinical-grade drug. At the completion of this program we will have the scientific data and regulatory approvals required to move forward with clinical trials, with the trial funding raised through private capital.
Therapeutic strategies aimed at different parts of the immune system thus far failed, or were only partially successful, largely because of the inability of drugs to cross over the "blood-brain barrier". This barrier protects the brain from harmful toxins, but in the case of potentially beneficial drugs it also prevents those drugs from reaching the brain where they are needed. We have generated a new system for delivering anti-inflammatory agents to the brain, by using a "gene delivery" system that teaches brain cells to produce the anti-inflammatory drug that the need themselves, bypassing the blood-brain barrier. Our data demonstrates that we can increase the number of "regulatory T cells" in the brain of treated mice. These are anti-inflammatory white blood cells that actively reduce inflammation in the brain and promote repair. Using a mouse model of traumatic brain injury, this treatment reduced the damage following injury by 50%. As there are currently no drugs available that prevent traumatic brain injury patients from secondary brain damage, a new drug with 50% protective capacity would have enormous social and economic impact, reducing the long-term cognitive loss in patients, improving the quality of life of carers, family and friends, and reducing the economic burden of injury by preventing long-term disability that impedes the ability to work and live independently.
In this grant we are seeking to develop this therapeutic approach for commercialisation. The drug is currently optimised for use in mice, and requires optimisation of a humanised version. We also need to initiate the regulatory process for testing in humans and the production process to manufacture clinical-grade drug. At the completion of this program we will have the scientific data and regulatory approvals required to move forward with clinical trials, with the trial funding raised through private capital.
Technical Summary
Traumatic brain injury (TBI) is a major unmet clinical need. Each year, there are 50 million TBIs globally. Great advances have been made in the emergency care of traumatic brain injury patients, increasing the survival rate to >90%. However following the acute injury, chronic inflammation drives neuronal death, contributing to long-term cognitive deficits and reduction in quality of life in ~50% of patients. As the leading cause of disability in young adults, this long-term impact globally costs US$400 billion per year.
Despite the scale of this clinical need, there are no effective medical treatments to prevent secondary neurological death in TBI patients. The brain presents a unique challenge in drug-delivery, which we have recently overcome with a novel delivery system for directing the production of biologics in the inflamed brain.
We recent identified an anti-inflammatory population of regulatory T cells in the brain of mice and humans, limited only by low levels of the biologic interleukin 2 (IL2). Combining our biologic delivery system with IL2 provision, we create a unique solution to limiting regulatory T cells numbers: with an inducible upregulation in the tissue surrounding injury sites. In the mouse model of TBI, we found this treatment reduced the developing lesion size by 50% and completely corrected the cognitive deficit induced. If translated to the human context, this would provide the first effective prevention of secondary neuronal death after TBI injury, profoundly improving the lives of patients.
In this grant we are seeking to develop this therapeutic approach for commercialisation. We will optimise a humanised version of the delivery system, complete efficacy studies, and initiate the regulatory and production process. At the completion of this program we will have the scientific data and regulatory approvals required to raise private capital for toxicology studies and clinical trials, via a spin-off company.
Despite the scale of this clinical need, there are no effective medical treatments to prevent secondary neurological death in TBI patients. The brain presents a unique challenge in drug-delivery, which we have recently overcome with a novel delivery system for directing the production of biologics in the inflamed brain.
We recent identified an anti-inflammatory population of regulatory T cells in the brain of mice and humans, limited only by low levels of the biologic interleukin 2 (IL2). Combining our biologic delivery system with IL2 provision, we create a unique solution to limiting regulatory T cells numbers: with an inducible upregulation in the tissue surrounding injury sites. In the mouse model of TBI, we found this treatment reduced the developing lesion size by 50% and completely corrected the cognitive deficit induced. If translated to the human context, this would provide the first effective prevention of secondary neuronal death after TBI injury, profoundly improving the lives of patients.
In this grant we are seeking to develop this therapeutic approach for commercialisation. We will optimise a humanised version of the delivery system, complete efficacy studies, and initiate the regulatory and production process. At the completion of this program we will have the scientific data and regulatory approvals required to raise private capital for toxicology studies and clinical trials, via a spin-off company.
