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Are we ready for successful clinical targeting of neuroinflammation?: major challenges and how to overcome them (#1202)
1 Eli Lilly and Company Limited, Neurodegeneration and Pain, Windlesham, United Kingdom
The study of the contribution of neuroinflammation to the onset and progression of neurological disorders, including Alzheimer’s, Parkinson’s and Pain, has undergone a revolution in recent years. Now, targeting neuroinflammation seems a plausible approach to provide disease-modifying therapies, and this is echoed by ongoing efforts of the pharmaceutical industry to progress neuroinflammation targets closer to the clinical space. However, there are significant challenges ahead of us, including restricted human validation of potential targets or the lack of specific fluid or imaging biomarkers that could be utilised to stratify and/or follow patient populations. Here we will discuss these and other challenges and potential solutions, to try to overcome the limitations of a relatively nascent therapeutic approach.
Keywords: Alzheimer’s disease, Immune Function, Neurodegenerative diseases
Microglia as drug targets in AD – what does it take? (#1127)
A. Mechling1, I. Knuesel1
1 F. Hoffmann-La Roche Ltd., Roche Innovation Center, Basel, Basel-Stadt, Switzerland
As the resident immune cells of the central nervous system, microglia play key roles in CNS maintenance, including refinement of synaptic networks, phagocytosis of cellular debris, and secretion of neurotrophic factors. They actively survey the environment for the presence of pathological elements such as neuronal death or protein aggregates1. On the other hand, their activation is not only essential to brain recovery and repair; sustained activation or deregulated responses may exacerbate brain injury and play a major role in neuronal cell damage and death by releasing a variety of inflammatory and neurotoxic mediators2-4. In addition, aged microglia undergo striking molecular changes which affect their neuroprotective functions, ultimately leading to a failure in proper damage response during aging and resulting in progressive neurodegeneration5. The full range of microglial activities is still not completely understood, but there is strong genetic evidence supporting a crucial role for both innate and adaptive immunity dysfunction in aging-associated neurodegenerative disorders6. The talk will cover recent progress in our understanding of both deleterious and beneficial effects of microglia in the setting of chronic neurological insults, and the emerging concepts surrounding pharmacological therapeutic interventions.
1 Knuesel et al. Nat Rev Neurol. 2014; 10:643-60.
2 Ramanan et al. Brain. 2015; 138:3076-88.
3 Kreisl et al. Brain. 2013; 136:2228-38.
4 Hamelin et al. Brain. 2016; 139:1252-64.
5 Streit and Xue. Curr Opin Immunol. 2014;29:93-6.
6 Gagliano et al. 2016, Ann Clin Transl Neurol. 2016;3:924-33.
Keywords: Immune Function, Microglial cells, Single cell RNA-Seq
Evolutionary Divergence and the Challenge of Validating Immune Targets in Alzheimer's Models (#1203)
D. V. Hansen1, W. J. Meilandt1, B. A. Friedman2
1 Genentech, Neuroscience, South San Francisco, California, United States of America
Common genetic variants associated with Alzheimer’s disease (AD) frequently confer only modest effects on disease risk, and how such variants affect the function of individual genes is often unknown. Therefore, a common approach to illuminate the role of AD-associated genes in disease pathogenesis is to abolish the function of those genes in mouse models of AD and observe changes in AD-related pathologies. Moreover, pharmaceutical efforts to advance novel AD therapies into the clinic often rely on studies of preclinical efficacy in mouse models. Such efforts to inform human AD pathomechanisms using mice are complicated by at least three critical differences between human AD and mouse models: etiology of disease, environmental diversity, and evolutionary divergence. In this workshop, I will discuss how evolutionary divergence in the logic of innate immune signaling can frustrate efforts to validate potential drug therapies aimed at immune-related targets inspired by AD genetic studies. I will also discuss disparities between microglial transcriptional profiles in human AD tissues versus mouse AD models, and how these may inform both our understanding of AD pathogenesis and the development of improved AD models.
Keywords: Alzheimer’s disease, Immune Function, Microglial cells
“May the force be with you” – Challenges in developing microglia-targeted therapeutics (#1163)
1 Axxam, Bresso/Milano, Italy
Despite microglia being identified 100 years ago, Pio Del Rio-Hortega (1919), our knowledge about microglial ontogeny and functions have only considerably advanced recently.
Microglia are an unusual subpopulation of cells among the mononuclear phagocytes representing approximately 10% of the total cells within the adult central nervous system. Microglia are not derived from bone marrow monocytes, but originate from erythromyeloid progenitors in the yolk sac. Once within the CNS, microglia find a highly specialized environment characterized by the presence of developing neurons and radial glia, but devoid of other glial cells.
Unlike any other tissue-resident macrophage, microglia are separated from the circulatory compartment by the blood brain barrier, and as such develop and survive for their entire lifespan without coming into contact with blood, unless there is a traumatic event.
Recent work has demonstrated, very elegantly, that the classical definition of microglia as ‘‘resting’’, used to describe physiological conditions, doesn’t fit with the current understanding. Even in healthy conditions, microglia never ‘‘sleep’’ but continuously monitor the surrounding environment.
Furthermore, microglia are selectively adapted to serve critical functions of the CNS by instructing programmed cell death and the removal of new neurons, or by pruning, elimination, and maturation of synapses.
The extreme flexibility and sensitivity of microglia, necessary to properly execute their job, are some of the reasons why drug discovery efforts are extremely challenging for these unique immune cells. The “new biology” around microglia will help to pave the way for new therapeutic routes. Drug discovery approaches based on these new emerging targets will be illustrated.
Keywords: Ion channels, Microglial cells, Neurodegenerative diseases
Glial P2X7 in health & disease: a drug discovery & development perspective (#1128)
1 Janssen R&D, Neuroscience, San Diego, California, United States of America
P2X7 is an ATP-gated ion channel, expressed abundantly in microglia within the CNS. Activation of P2X7 leads to IL-1β release via the NLRP3 inflammasome. In recent years, the P2X7-NLRP3-IL1β pathway has received tremendous attention in the context of neuroinflammatory disorders such as observed in Alzheimer's, epilepsy, multiple sclerosis and mood disorders. To that end, significant progress has been made with brain penetrant P2X7 antagonists; the talk will highlight the drug discovery program at Janssen culminating in P2X7 clinical candidates (1, 2). SAR supporting in-vitro and in-vivo assays focusing on readouts of P2X7 target engagement in the animal brain will be shared with the audience. Relationships of plasma concentration of the compounds with CNS target engagement helped the discovery team to select doses for efficacy studies. In parallel, blood -based biomarker and PET ligands were used to understand occupancy and translate preclinical knowledge to a clinical setting.
The Janssen Neuroscience Discovery and Early Development team
Keywords: Cytokine production, Ion channels, Microglial cells