Virtual Poster Session
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Je Min Yoo, PhD; Donghoon Kim, PhD,
Graphene Quantum Dots (GQDs) as a therapeutic agent for treating Niemann-Pick Disease Type C
While the neuropathological characteristics of Niemann-Pick disease Type C (NPC) result in a fatal diagnosis, development of clinically available therapeutic agents remains a challenge. Here we propose graphene quantum dots (GQDs) as a potential candidate for the impaired functions in NPC in vivo. In addition to the previous findings that GQDs exhibit negligible long-term toxicity as well as their capability to penetrate the blood-brain barrier (BBB), GQDs treatment reduces the aggregation of cholesterol in the lysosome through expressed physical interactions. GQDs also promote autophagy and restore defective autophagic flux, which in turn decreases the atypical accumulation of autophagic vacuoles. More importantly, the injection of GQDs inhibits loss of Purkinje cells in the cerebellum while also demonstrating reduced activation of microglia. The ability of GQDs to alleviate the impaired functions in NPC proves the promise and potential in the use of GQDs toward resolving NPC and other related neurodegenerative disorders.
Daniel Alkon, M.D.
President & Chief Scientific Officer
Dr. Daniel Alkon, M.D. has spent the past 30 years directing programs on the molecular and structural basis of associative memory at the National Neurologic Institute of NIH and is a Founding Scientific Director of the Blanchette Rockefeller Neuroscience Institute. He and his teams developed neurorestorative therapeutics for degenerative disorders of the central nervous system, as well as non-invasive Biomarkers for Alzheimer's Disease. Dr. Alkon has also served as the Toyota Chair of Neurodegenerative Diseases, Professor of Neurology at West Virginia University, and was a Research Professor at Johns Hopkins University. Dr. Alkon received his B.A. from the University of Pennsylvania, and his M.D. at Cornell University.
Multi-modal AD Regenerative Therapeutics for Alzheimer's Disease and Degeneration in Other Neurological Disorders
Alzheimer's Drug candidates have been developed to regulate a broad range of targets: A Beta oligomers, amyloid plaques, hyperphosphorylated tau, neurofibrillary tangles, cholinergic synaptic function, and glutamatergic synapses. To date, none of these candidates have been approved by the FDA to prevent and treat the underlying disease and to actually improve cognitive function(s). Synaptogenix, building on decades of basic research at the NIH and the Rockefeller Neurosciences Institute, has pursued a program that begins with molecular cascades responsible for associative memory storage - a primary symptomatic deficit of early AD. Memory cascades identified by Synapotgenix scientists were enhanced by activating the a PKC epsilon-Synaptic Growth Factor cascade that ultimately increases the numbers of fully mature mushroom spine synapses. Bryostatin, the lead Synaptogenix drug, activates PKC epsilon which, in turn, activates many synaptic growth factors that include BDNF, NGF, HGF, IGF, and GAP 43 that lead to synaptogenesis and cognitive enhancement in pre-clinical models of Alzheimer's disease, Multiple Sclerosis (MS), Parkinson's disease (PD), and other neurodegenerative conditions. Bryostatin-PKC epsilon activation, however, has also been demonstrated with in vitro and in vivo preclinical studies to have multi-modal efficacy that includes reduction of A Beta and amyloid plaques, reduction of oxidative stress and inflammation, and also reduction of hyperphosphorylated tau and neurofibrillary tangles. Biochemical downstream consequences of PKC epsilon includes increased activity of all 3 major A Beta degrading enzymes (ECA, IDE, and neprilysin), reduction of GSK-3 Beta (the major tau phosphorylating enzyme, and blocking of BCl-2 responsible for apoptosis. With in vivo preclinical animal studies Bryostatin was shown by Synaptogenix scientists and others in independent laboratories to neutralize etiologic factors in AD, PD, ALS, MS, Fragile X autistic spectrum disorder, TBI (traumatic brain injury), and stroke. In recent pilot clinical trials, Bryostatin produced clear signals of improvement in the Severe Impairment Battery (SIB) scores of advanced AD patients (p<.01, 2-tailed, pre- specified exploratory analyses). The multiplicity of Bryostatin benefits, therefore, potentially addresses not only causal factors in a broad spectrum of neurodegenerative disorders, but also the destructive consequences of these disorders on synaptic and neuronal elimination. These results suggest that the PKC epsilon - BDNF cascades are central to and critical for the maintenance of synaptic and neuronal vitality, thereby offering a gateway to the preservation, regeneration of, and restoration of the brain's circuitry. This pathway's molecular targets, therefore, could offer broad benefit for regenerating this circuitry in conditions of brain degeneration - as described in a recent review (Sun and Alkon, 2019, Trends in Pharmacological Sciences, Sept. , V. 40, #9). Figures to be provided.
Muhammad Kaiser Abdul Karim1, Tony Oosterveen1, Dumitra Bors1, Tuzer Kalkan1, Imbisaat Geti1, Giacomo Borsari1, Petra Parac1, Michael D’Angelo1, Tonya Frolov1, Farah Patell-Socha1, Nikolaos Patikas2, Sarah Cooper3, Grant Belgard1, Thomas Moreau1, Andrew Bassett3, Emmanouil Metzakopian2, Mark Kotter1
2 UK Dementia Research Institute, University of Cambridge
3 Wellcome Trust Sanger Institute
Optimized reprogramming of human iPSCs to generate distinct neuronal subtypes
Human brains differ remarkably in size and cellular composition from rodent models used in pre-clinical research. For example, human cortical neurons have larger dendritic trees, distinct electrophysical properties and express different protein isoforms. For neuronal indications, less than 10% of findings derived from animal models can be translated to the clinic*. A robust source of human iPSC-derived neurons would offer an attractive in vitro model for basic research and high content drug screens, which could reduce costs, improve screen specificity, and accelerate drug development. However, conventional iPSC differentiation protocols are often complex inconsistent, and difficult to scale. To overcome these problems, we developed a proprietary gene-targeting strategy, opti-ox**, that enables highly controlled expression of transcription factors to rapidly reprogram human iPSCs (hiPSCs) into pure somatic cell types. We have manufactured consistent and homogenous cultures of glutamatergic neurons (>80% VGLUT1/2) and GABAergic neurons (VGAT1, GABA), which show homogenous molecular phenotype at single cell transcriptomics resolution. Reprogramming is highly consistent and synchronised, yielding fully functional neurons in less than 14 days. Our technology opens up novel avenues for the development of in vitro models to support research and healthcare innovations. -- References: * Vargas-Caballero M, et al., Expert Opin Drug Discov. 2016;11(4):355-67 ** Pawloski M, et al. Stem Cell Reports. 8(4), 803-812, 2017.
Sharon Rosenzweig-Lipson - AgeneBio; Russell Barton - AgeneBio; Michela Gallagher - AgeneBio and Johns Hopkins University; Chris J. Edgar - Cogstate; Paul Maruff - Cogstate; Richard Mohs - AgeneBio
HOPE4MCI Trial: First Trial Targeting Reduction of Hippocampal Overactivity to Treat Mild Cognitive Impairment due to Alzheimer’s Disease with AGB101
HOPE4MCI Trial: First Trial Targeting Reduction of Hippocampal Overactivity to Treat Mild Cognitive Impairment due to Alzheimer’s Disease with AGB101 Sharon Rosenzweig-Lipson, Russell Barton, Michela Gallagher, Chris J Edgar, Paul Maruff, Richard Mohs Recent clinical trials for Alzheimer’s disease, including prodromal AD, have struggled to achieve clinical efficacy despite performing as expected with respect to amyloid molecular targets. The development of therapeutics has now focused on pathological tau which spreads according to Braak staging in a manner consistent with the progression of neurodegeneration and clinical decline in AD patients. Given the centrality of a condition of neural hyperactivity in the hippocampus/medial temporal lobe as a driver of AD pathology and early cognitive impairment, hyperactivity has emerged as a rational therapeutic target in early disease. There is strong support from preclinical AD models and human patients, particularly in early stages of AD, that neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology and brain dysfunction. It is noteworthy that aging itself, which represents the greatest risk for sporadic late onset AD, is associated with modestly elevated hippocampal neuronal activity in both aged memory-impaired rodents and non-human primates. Those findings translate in human neuroimaging to a corresponding increase in age-related hippocampal activation detected by fMRI, a condition that is dramatically augmented in patients with amnestic MCI. The notion that AD pathology contributes to the augmentation of hippocampal hyperactivity is supported by the clinical finding that hyperactivity is most pronounced in the MCI clinical/cognitive phase in patients with amyloid positive PET imaging compared to those who are amyloid negative. Further, AD pathophysiological pathways involving both amyloid and tau have been functionally linked to excessive neural activity, with heightened neural activity causing dysfunction and progressive spread of pathology in the disease from an origin in the medial temporal lobe/hippocampus. Like hippocampal overactivity, recent evidence has demonstrated an association of amyloid and p-tau 217 in early disease, with progressive elevation of p-tau217 through preclinical, prodromal, and clinical phases with remarkable specificity of p-tau217 for AD relative to other tauopathies. Substantial clinical evidence also indicates that hippocampal overactivity longitudinally predicts subsequent cognitive decline/conversion to a dementia diagnosis and is significantly correlated with the extent of neuronal injury affecting the brain. The evidence that hippocampal overactivity is a potential driver of neurodegeneration during prodromal AD supports the reduction of overactivity as a novel approach to the treatment of patients in this phase of disease with potential to delay/slow progression (Figure 1, Poster). Clinical proof of concept for this therapeutic hypothesis was demonstrated with AGB101 (low dose levetiracetam) in a Phase 2A study that showed a reduction in hippocampal overactivity resulted in improvement in task related memory performance3. Further benefit of this approach is supported by a recent preclinical study demonstrating that chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces both Aβ and tau pathology in the hippocampus7. To further examine this hypothesis, AGB101 is currently being tested in a 78-week protocol using tau biomarkers ([11C]MK 6420 pet imaging and p-tau 217 plasma) alongside CDRsb for clinical/cognitive efficacy in MCI due to AD. Partially supported by 5R01AG061091 to Richard Mohs and R01AG048349 to Michela Gallagher
Henrik H. Hansen, Johanna Perens, Urmas Roostalu, Jacob Lercke Skytte, Casper Gravesen Salinas, Pernille Barkholt, Ditte Dencker Thorbek, Kristoffer T. G. Rigbolt, Niels Vrang, Jacob Jelsing & Jacob Hecksher-Sørensen
Gubra, Hørsholm Kongevej 11B, 2970 Hørsholm Denmark.
Developing a high capacity pipeline for quantitative whole brain imaging in pre-clinical research
Rodent models are an important tool in preclinical drug development of neurological disorders. However, the complexity of the brain often complicates the qualification of drug efficacy and consequently there is an urgent need for technologies that can speed up informed decision making. Results: Here we present a high capacity pipeline for pre-clinical drug discovery that enables fast and reliable screening of drug effects. Using a combination of whole-brain immunolabelling, light sheet fluorescence microscopy (LSFM), registration to a common reference atlas and cloud based data reporting. Conclusion: Using this pipeline it is possible to quantify the total number of neurons, plaques or biodistribution across large study groups. Allowing for drug testing in mouse models of Parkinson’s disease, Alzheimer’s and other neurological disorders.
Viji Chelliah1, Cesar Pichardo1, Sreeraj Macha2,3, Peter Bloomingdale2, Nitin Mehrotra2, Piet van der Graaf1
1Certara QSP, United Kingdom; 2Merck, United States; 3Sanofi, United States
QSP model for axonopathy: can HDAC6 inhibitors improve axonal transport and delay ALS progression?
Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Impaired microtubule stability and defects in axonal transport of synaptic vesicles and organelles are early indicators in the pathogenesis of ALS. Studies have shown that HDAC6 inhibitors will be clinically effective in maintaining the integrity of the axons by stabilising microtubules and delay the progression of ALS. Here, we present a quantitative systems pharmacology model (QSP) that describes the key mechanism of HDAC6 resulting axonal transport defects. We then used the model to investigate whether HDAC6 inhibitors would reverse axonal transport deficit and delay progression of ALS. The model suggested that the inhibition of HDAC6 can have a positive effect on axonal transport and provided insights on additional biomarkers that are important for regulating axonal transport.
Dr. Dan Elbaum1 , Dr. Sandy Hinckley1 , Dr. Emanuele Sher3 , Dr. Birgit Priest2 , Dr. Mark Chappell2 , Helen Szekeres3 , Maria Whatton3 , Dr. Andrew Williams3 , Dr. Yu-Hua Hui2 , Dr. Matthew Abernathy2 , Dr. Keith Phillips2 , Louisa Appel3 , Dr. Keith Wafford3 , Dr. Kasper Roet1
1: QurAlis, Cambridge, United States
2: Eli Lilly and Company, Indianapolis, United States
3: Eli Lilly and Company, Basingstoke, United Kingdom
QRA-244 a Potent, Selective KCNQ2/3 Opener and a Potential Therapy for ALS patients
Recent studies have demonstrated that approximately half of ALS patients show hyperexcitability in the motor cortex and spinal motor axons, a phenotype that is linked to poor survival. ALS patients with motor system hyperexcitability can be targeted using neurophysiological biomarkers. In patient iPSC derived motor neurons this hyperexcitability leads to neurodegeneration and was traced to reduced Kv7.2/7.3 activity. This motor neuron degeneration was rescued by the Kv7.2/7.3 agonist Retigabine which also reversed hyperexcitability in a clinical trial of ALS patients. The trial demonstrated a statistically significant beneficial effect on several markers of excitability including short interval cortical inhibition (SICI) and strength duration time constant (SDTC), two biomarkers linked to patient survival. Despite these beneficial effects, retigabine was associated with significant adverse events consistent with its prior clinical use in epileptic patients which strongly limits its use as a therapeutic. We have been working to discover, characterize, and develop a novel KCNQ2/3 activator with an improved channel specificity, which is expected to translate into a better clinical safety profile with comparable or better efficacy. Here we show that QRA-244 activates KCNQ2/3 channels selectively in the KCNQ family, increases rheobase and decreases SDTC in rats. In side by side experiments with Retigabine we demonstrate a significantly improved safety profile in rat models of dizziness (rotarod) and fatigue (REM/NREM sleep). Unlike Retigabine, QRA-244 has no effect on human bladder strips at clinically relevant concentrations. Overall, QurAlis is developing QRA-244, a more potent and selective Kv7.2/7.3 activator aimed at normalizing excitability of the ALS motor system, with a significant reduction in off-target driven adverse events. We believe that this compound offers a promising therapeutic approach to counteract disease progression induced by hyperexcitability in ALS patients.