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The origin and progression of many neurodegenerative diseases is not clearly understood, and basic research is required to provide a platform for development of effective therapies. Amyotrophic Lateral Sclerosis (ALS) is an incurable progressive disease of motor neurons in the spinal cord and brain, being associated with dysfunctional microglia. The purpose of this research proposal is to address this unmet need using a dual therapeutic platform approach aiming to modulate the activity of disease-associated microglia. Based on several years of our research into microglial biology and development of immunotherapies, the aim of our research programme is to develop novel immunotherapies including (i) enforced cellular repopulation of the CNS, in which we will replace microglia with transplanted healthy cells, and (ii) cuttimg-edge nanobiologics delivering specific immunomodulatory drugs that will specifically modify microglial function. We will develop protocols for such therapies and investigate the immunomodulatory effects at molecular and functional levels in both in vitro brain organoid cell culture systems and in vivo in experimental models of ALS. We envisage that these therapeutic platforms will be applicable to a range of neurodegenerative diseases. Not only will these platforms provide potential personalised immunotherapies for translation into the clinic but will also greatly increase our understanding of the molecular cues governing microglial colonization of the CNS.

Tumors suppress the host's immune system. Breaking this immunosuppression is important for effective tumor therapy. Nanoparticles that contain softening molecules or tumor-killing chemicals are a new form of specific therapy that can be used to achieve immunosuppression. We have previously identified some of the most important molecules and genes that need to be silenced to prevent the development of immunosuppression and to prevent the growth of brain tumors. We will develop new gene-silencing molecules, so-called RNAi, nanoparticles for the treatment of brain tumors. The technology for this development is already established and patented. A number of molecules in the brain tumor will be blocked while delivery of a tumor-killing substance is delivered. We will try different combinations of these different agents to develop an effective protocol for the treatment of brain tumors. The technique will also be tested in melanoma and could be used with various cancers. People with GBM die on average within 2.5 years after diagnosis. We strive to improve survival by combining new therapeutic options for inhibition of immunosuppression in parallel with tumor-killing treatment. Nanoparticles will be used to deliver specific immunomodulatory agents, and different types of nanoparticles will be tested so that an optimal variant can be selected. We will first explore this concept in animal models with the long-term goal of translating the therapy to the clinic and thereby dramatically increase the life expectancy of people with brain tumors.

During inflammation the balance/imbalance of pro- and anti-inflammatory cellular activities will decide outcome – disease progression or healing. In patients with chronic inflammatory diseases there is an imbalance. Injecting pre-activated macrophages will restore this immunological imbalance. We have demonstrated that transfer of immunosuppressive macrophages modulates autoimmune diseases and have recently extended the myeloid cell therapy platform to include use of adult microglia. In cancer settings transfer of immunoactivated macrophages will reduce immunosuppression associated with the tumor environment and enable effective tumor killing Our goal is to provide proof-of-concept in an experimental model of glioblastoma brain tumors that effective therapy can be conducted using adoptive transfer of myeloid cells. Combined transfer of pre-activated, pro-inflammatory cells directly into the brain as well as peripherally will serve to enable mounting of an efficient anti-tumor immune response that will be not be suppressed by the tumor. We will study the immunological mechanisms involved in vitro by studying macrophage and TAMs. This project not only give us to better understanding of fundamental tumor immunobiological processes, but will also be directly translatable to the clinic Individuals with GBM are usaully dead with 2.5 years of diagnosis - we aim to increase that life expectancy dramatically through establishment of a clinical protocol that is repeatable due to use of an individual's own blood cells.

During inflammation the balance/imbalance of pro- and anti-inflammatory cellular activities will decide outcome – disease progression or healing. In patients with chronic inflammatory diseases there is an imbalance. Injecting pre-activated macrophages will restore this immunological imbalance. We have demonstrated that transfer of immunosuppressive macrophages modulates autoimmune diseases and have recently extended the myeloid cell therapy platform to include use of adult microglia. In cancer settings transfer of immunoactivated macrophages will reduce immunosuppression associated with the tumor environment and enable effective tumor killing Our goal is to provide proof-of-concept in an experimental model of glioblastoma brain tumors that effective therapy can be conducted using adoptive transfer of myeloid cells. Combined transfer of pre-activated, pro-inflammatory cells directly into the brain as well as peripherally will serve to enable mounting of an efficient anti-tumor immune response that will be not be suppressed by the tumor. We will study the immunological mechanisms involved in vitro by studying macrophage and TAMs. This project not only give us to better understanding of fundamental tumor immunobiological processes, but will also be directly translatable to the clinic Individuals with GBM are usaully dead with 2.5 years of diagnosis - we aim to increase that life expectancy dramatically through establishment of a clinical protocol that is repeatable due to use of an individual's own blood cells.