Development of a humanised delivery system for interleukin 2 to treat traumatic brain injury

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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.