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THURSDAY, JUNE 9
7:20 am Continental Breakfast Breakout Discussions
Breakout Discussion Topics:
Impact of Using Induced vs. Transgenic Models
Biomarker Discovery: How Close are we?
Concomitant Drugs: Will the Next PD Drug be Drugs…?
8:20 Chairperson’s Remarks
8:30 The Biochemistry of LRRK2 Reveals New Opportunities for Regulating Its Activity
Matthew J. LaVoie, Ph.D., Assistant Professor of Neurology, Brigham and Women’s Hospital and Harvard Medical School
We propose a model whereby LRRK2 function is regulated via its membrane localization, dimerization, and the subsequent activation of its kinase function. This model suggests multiple opportunities for the therapeutic modulation of LRRK2 function, independent of kinase inhibition. These data also have implications for the future identification of bona fide LRRK2 substrates, the biochemical composition and nature of active LRRK2, and LRRK2 function within the cell.
9:00 LRRK2 Genetics and the Impact on Parkinson’s Drug Development
Alastair D. Reith, Ph.D., Director, External Alliances & Development, R&D China, Medicines Research Centre, GlaxoSmithKline (INVITED)
9:30 LRRK2 cell biology: Basic Research Towards Parkinson's Disease Therapeutics
Wanli W. Smith, M.D., Ph.D., Assistant Professor, Head, Molecular Neuroscience Laboratory, Pharmaceutical Sciences, University of Maryland School of Pharmacy
We have explored the LRRK2 cell biology and generated the LRRK2 cell and Drosophila models for Parkinson’s disease. We have used these models to screen and test the potential novel small molecules to target LRRK2 activity resulting in neuronal protection and suppression of the PD-like symptoms. Our findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease modifying effect, suggesting that inhibition of LRRK2 holds promise as a treatment for PD.
10:00 Networking Coffee Break in the Exhibit Hall
10:45 The Inhibition of a-Synuclein by Regulating its Translation Level
Maria Maccecchini, Ph.D., President & CEO, QR Pharma
We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5’UTR driven luciferase expression. In this screen several compounds selectively blocked SNCA expression in neural cells (Posiphen and the cardiac glycoside, strophanthidine <1 uM IC50). Thus, Posiphen, a known APP-directed lead, has potential use as a SNCA inhibitor in PD therapy.
11:15 Targeting Nuclear Hormone Receptors to Treat Neurodegenerative Disease
Ethan S. Burstein, Ph.D., Director, Biosciences, ACADIA Pharmaceuticals
We have established a portfolio of assets that address many aspects of neurodegenerative disease ranging from symptomatic relief to neuroprotection. We are developing a group of pre-clinical assets with disease modifying potential in Parkinson’s disease and Alzheimer’s disease including estrogen receptor beta (ERb) selective agonists, selective androgen receptor modulators (SARMs), and novel Nurr1-RXR agonists. Highlights of these programs will be presented.
11:45 Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own
1:15 pm Chairperson’s Remarks
1:25 Novel mGluR4 Positive Allosteric Modulators in Parkinson’s Disease
Ian J. Reynolds, Ph.D., Senior Director, Neuroscience, Merck Research Laboratories
1:55 The Discovery and Development of Positive Allosteric Modulators of MGlu4 for the Treatment of Parkinson’s Disease
Corey R. Hopkins, Ph.D., Research Assistant Professor, Associate Director of Medicinal Chemistry, Drug Discovery Program, Vanderbilt Program
Using a functional high-throughput screening and subsequent parallel synthesis approach, we have discovered a novel series of positive allosteric modulators of mGlu4. Optimized compounds provide excellent brain exposure after dosing and have robust in vivo efficacy in reversing haloperidol-induced catalepsy, an anti-Parkinsonian rodent model. This series of selective positive allosteric modulators of mGlu4 provides critical research tools to further probe the mGluR4-mediated effects in Parkinson’s disease.
2:25 Ice Cream Refreshment Break in the Exhibit Hall
3:05 Iron, Tau and DJ-1: Insights into the Mechanism of Action of PBT-434 in Parkinson’s Disease Mouse Models
Ashley I. Bush, M.D., Ph.D., Director, Oxidation Biology Laboratory, Mental Health Research Institute, Victoria, Australia; Professor of Pathology, University of Melbourne; Lecturer in Psychiatry, Harvard Medical School, Massachusetts General Hospital; Adjunct Professor of Neuroscience, Cornell University Medical Center, New York
Iron elevation in the substantia nigra (SN) is a feature of Parkinson’s disease (PD) and animal models, but the cause was uncertain. Genetics and neuropathology implicate tau in PD. We found that tau knockout mice develop a clear parkinsonian phenotype with age, accompanied by elevated SN neuronal iron caused by obtunded APP trafficking. Oral PBT-434 (Prana Biotechnology Ltd) prevents SN iron elevation in MPTP and 6OHDA mouse models, while elevating DJ1 and rescuing the phenotype when administered days after the toxin. PBT-434 is not a strong chelator. These data underscore the value of restoring SN iron homeostasis as a promising therapeutic approach for PD.
3:35 Modulating Synuclein Phosphorylation as a Potential Disease Modifying Approach for Parkinson’s Disease
Marcelle Bergeron, Ph.D., Director, Neuropharmacology, Elan Pharmaceuticals, Inc.
a-Synuclein phosphorylated at Ser129 (Phospho-Syn) is the most prevalent & consistent synuclein modification observed in Parkinson’s disease (PD) pathology & dementia with Lewy bodies. It is also a feature of synuclein inclusions in transgenic mouse & fly PD models. Whether Phospho-Syn promotes or inhibits a-synuclein aggregation & neurotoxicity in vivo is still unknown. Therefore identifying the enzymes responsible for a-synuclein phosphorylation could help develop tools to define the role of Phospho-Syn in PD & other synucleopathies. Aside from the G-protein-coupled receptor kinases (GRK5 & GRK6) & casein kinase II, the polo-like kinase (PLK) family members (in particular PLK2 & PLK3) have been proposed as the main enzymes responsible for a-synuclein phosphorylation at Ser129. To better understand the role of PLKs in a-synuclein phosphorylation, this presentation will focus on recent studies evaluating the effect of genetic & pharmacological PLK knockdown on Phospho-Syn levels in brain.
4:05 Animal Model of Presymptomatic Parkinson’s Diseases
Craig Ferris, Ph.D., Professor, Psychology and Pharmaceutical Sciences, Director, Center for Translational NeuroImaging, Northeastern University
Data will be presented on a rat model of presymptomatic PD that recapitulates disease progression from early redox stress and microglia activation to Lewy body formation. Animals appear to be healthy yet show a 20% reduction in dopamine neurons in the substantia nigra compacta, loss of tyrosine hydroxylase staining in the dorsal striatum, subtle changes in motor activity and loss of olfactory discrimination as determined by fMRI. SPECT imaging for the dopamine transporter shows a modest increase in binding.
4:35 End of Conference
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