Biology of Aging Program-05.9.14

8/18/2019 Biology of Aging Program-05.9.14

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The Alzheimers Drug Discovery Foundation and the Brain Dysfunction Discussion Group at theNew York Academy of Sciences present:

The Biology of Aging: Novel Drug Targets for Neurodegenerative Disease

Friday May 9, 2014 • 8:00 AM–5:00 PMOrganizers:

Howard Fillit, MD, The Alzheimers Drug Discovery FoundationKevin J. Lee, PhD, Lawrence Ellison FoundationJennifer S. Henry, PhD, The New York Academy of Sciences

8:00 am Registration and Continental Breakfast

8:45 am Welcome and Opening RemarksJennifer S. Henry, PhD, The New York Academy of SciencesHoward Fillit, MD, The Alzheimers Drug Discovery Foundation

Kevin J. Lee, PhD, Lawrence Ellison Foundation

Session I. Plenary Talk

9:00 am Delaying the Biology of Aging to Prevent Alzheimer’s DiseaseNir Barzilai, MD, Albert Einstein College of Medicine

9:20 am Q&A session

Session II. Major Pathways and Novel Targets in Aging Biology

9:30 am Autophagy, Cell Health and AgingEric H. Baehrecke, PhD, University of Massachusetts Medical School

9:50 am Q&A session

10:00 am Aging and mTOR: Challenges in Sustaining Metabolic and Protein HomeostasisBrendan D. Manning, PhD, Harvard School of Public Health

10:20 am Q&A session

10:30 am Networking coffee break

11:00 am Proteostasis in Biology, Aging, and Disease

Richard I. Morimoto, PhD, Northwestern University11:20 am Q&A session

11:30 am Role of Complement Cascade in Synapse Loss and Cognitive AgingBeth Stevens, PhD, Harvard Medical School

11:50 am Q&A session

12:00 pm Networking lunch break and poster session

All poster presenters should stand by their posters 12:30–12:55 pm


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Session III. From Aging Biology to Drug Development for Neurodegenerative Disease

1:00 pm The Anti Aging Protein Klotho as a New Target for Treating Neurodegenerative DiseasesCarmela R. Abraham, PhD, Boston University

1:20 pm Q&A session

1:30 pm Stimulation of Macroautophagy with Small MoleculesHaung Yu, PhD, Columbia University

1:50 pm Q&A session

2:00 pm A New Mitochondrial Target for Neurodegenerative DiseaseJerry Colca, PhD, Metabolic Solutions Development Company

2:20 pm Q&A session

2:30 pm Networking coffee break

3:00 pm Targeting Neuroinflammation by Inhibiting Glial Cell Cytokine OverproductionD. Martin Watterson, PhD, Northwestern University Feinberg School of Medicine

3:20 pm Q&A session

3:30 pm Biological and Chemical Approaches to Adapt Proteostasis to Ameliorate ProteinAggregation DiseasesJeffrey W. Kelly, PhD, Scripps Research Institute

3:50 pm Q&A session

4:00 pm Networking reception

5:00 pm Close

DISCLOSURES: All speakers and organizers participating in this activity are required to disclose to theaudience any significant financial interest and/or other relationship with the manufacturer(s) of any commerciaproduct(s) and/or provider(s) of commercial services discussed in his/her presentation and/or the commerciacontributor(s) of this activity.

Carmela R. Abraham NoneEric H. Baehrecke NoneNir Barzilai Consultant and Share Holder: COHBAR Inc.

Jerry Colca Employee: Metabolic Solutions Development CompanyHoward Fillit NoneJennifer S. Henry NoneJeffrey W. Kelly Consultant and Share Holder : Pfizer, Proteostasis Therapeutics, Misfolding

Diagnostics, Inc.Other Financial Support: Pfizer

Kevin J. Lee NoneBrendan D. Manning NoneRichard I. Morimoto NoneBeth Stevens NoneD. Martin Watterson NoneHaung Yu Other Financial Support: Merck, MINT


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Organizers:Howard Fillit, MD, The Alzheimers Drug Discovery FoundationHoward Fillit, MD is an internationally recognized geriatrician and neuroscientist and expert in Alzheimer’sdisease. He is the founding Executive Director and Chief Science Officer of the Alzheimer’s Drug DiscoveryFoundation (ADDF), a not-for-profit corporation whose mission is to rapidly accelerate the discovery anddevelopment of drugs to prevent and treat Alzheimer’s disease. Dr. Fillit has had a distinguished academic

medicine career and is currently a clinical professor of geriatric medicine and palliative care, medicine andneurosciences at The Mount Sinai Medical Center in NYC. Throughout his career, Dr. Fillit has maintained alimited private practice in consultative geriatric medicine with a focus on Alzheimers disease. He has alsoserved as a consultant, founder, member of the Board of Directors, and member of the Scientific and Clinica

Advisory Boards for pharmaceutical, biotechnology and health care companies. Dr. Fillit has receivednumerous awards, including the Alzheimers Associations Rita Hayworth Award for Lifetime Achievement. Heis a fellow of the American Geriatrics Society, the American College of Physicians, the Gerontological Societyof America, and the New York Academy of Medicine. He is the author or co-author of more than 300 scientificarticles, abstracts and books, including the leading international Brocklehurst’s Textbook of Geriatric Medicineand Gerontology . He has given hundreds of speeches throughout the world on topics related to research andclinical care in geriatric medicine and Alzheimers disease.

Kevin J. Lee, PhD, Lawrence Ellison FoundationDr Lee is Executive Director of the Lawrence Ellison Foundation, a philanthropic organization established tosupport biomedical research on the fundamental mechanisms of aging, age-related diseases, andneuroscience. The Lawrence Ellison Foundation is the philanthropy of Larry Ellison, founder and CEO oOracle Corporation. Dr Lee is a graduate of the University of Michigan and received his PhD in biology fromthe Massachusetts Institute of Technology. His career spans over 25 years of research experience inmolecular genetics and neurobiology in biotechnology, academic research and not-for-profit settings. He wasappointed Executive Director of the Foundation in September 2012, having served as Deputy ExecutiveDirector from 2007-2012. Prior to joining the Ellison Medical Foundation, Dr Lee served as Executive VicePresident-Research of Sentigen Biosciences. He was responsible for the start-up and development of this NewYork City-based biotechnology company leading to its acquisition by Invitrogen Corporation in 2006. He has

served as a member of the Scientific Review Board for the Simons Foundation Autism Research Initiative inNew York. Dr Lees scientific research career employed genetic approaches to learn how neurons in the brainare “wired up” during development to make functional circuits that relay sensory information and controlbehavior. He worked with Dr Thomas Jessell in the Center for Neurobiology and Behavior at ColumbiaUniversity, where he studied the specification, axonal projection, and functional connectivity of nerve cells inthe spinal cord. He is the recipient of biotechnology patents and is the author of numerous researchpublications.

Jennifer Henry, PhD, The New York Academy of SciencesJennifer Henry, PhD, is the Director, Life Sciences at The New York Academy of Sciences. Dr Henry joined the

Academy in 2009, prior to which she was a Publishing Manager in the Academic Journals division at Nature

Publishing Group. She also has eight years of direct editorial experience as Editor of Functional Plant Biologyfor CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University ofMelbourne, specializing in the genetic engineering of transgenic crops. As Director of Life Sciences, she isresponsible for developing scientific symposia across a range of life sciences, including biochemicapharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology, underthe auspices of the Academy’s Frontiers of Science program. She also generates alliances with organizationsinterested in developing programmatic content.


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Abstracts and speakers:

Session I. Plenary Talk

Delaying the Biology of Aging to Prevent Alzheimer’s DiseaseNir Barzilai, MD, Albert Einstein College of Medicine

Aging is the major risk not only for AD but also for other diseases such as cancer, type 2 Diabetes mellitus andcardiovascular disease. We hypothesize that a progress in preventing these diseases will occur only if we can

understand the reason people age at different rates, and develop strategy to delay aging. We present 2examples. We study the genome of centenarians, whose aging and onset of its diseases have been delayed.We have implicated a longevity genotype, cholesterol ester transfer protein (CETP), in the preservation ocognitive function in centenarians and their families. CETP inhibitor is in phase III trial to prevent CVD butoffers an approach for prevention of AD. We have discovered line of, previously un-noted mitochondriaderived peptides, whose expression declines with aging. Those peptides have roles in metabolism and stressresponse. One of those peptides, humanin, has been directly implicated in neuronal toxicity relevant to ADDerivation of this molecule is tested for potential drug development for AD. These examples suggest anapproach of delaying aging and several of its disease, rather than focus on one organ-specific drug at a time.

Dr Barzilai is a Professor of Medicine and Genetics and the Director of the Institute for Aging Research at the Albert Einstein College of Medicine the home of 2 Centers of excellence for the Biology of Aging. His interests

focus on several basic mechanisms in the biology and genetics of aging. Among others, his studies on familieswith centenarians have provided genetic/biological insights on the protection against aging. Several drugs aredeveloped based, in part, on these paradigm-changing studies. Dr Barzilai was awarded over $35MM NIHfunding for these efforts, has published over 200 peer-reviewed papers, and is a recipient of numerousprestigious awards, including the recipient of the 2010 Irving S. Wright Award of Distinction in Aging Research.

Session II. Major Pathways and Novel Targets in Aging Biology

Autophagy, Cell Health and AgingEric Baehrecke, PhD, University of Massachusetts Medical School

Autophagy is a catabolic process that targets cytoplasmic components for degradation by the lysosome

Autophagy is an important cellular response to stress, and plays essential roles in development, agingimmunity, cancer and neurodegeneration. Thus, autophagy is considered a promising target for diseasetherapies. Studies of yeast led to the identification of conserved factors that regulate autophagy, but the role ofautophagy in specific cell contexts during aging of multi-cellular organisms has not been rigorously studied.Recent studies of autophagy and how this process contributes to stem cell, tissue and organism health duringaging will be presented.

Eric Baehrecke obtained his PhD from the University of Wisconsin - Madison, and was a Howard HughesMedical Institute Fellow of the Life Sciences Research Foundation at the University of Utah during hispostdoctoral studies. He was a faculty member of the University of Maryland from 1995-2007, and is currentlyProfessor and Vice Chair of the Department of Cancer Biology at the University of Massachusetts MedicalSchool. His team studies the regulation and function of autophagy in cell survival and cell death.

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Aging and mTOR: Challenges in Sustaining Metabolic and Protein HomeostasisBrendan D. Manning, PhD, Harvard School of Public HealthMetabolic processes within cells must be managed by integrated control mechanisms that sense the nutrientstatus of both the cell and organism. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is akey signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinatedregulation of cellular metabolism. mTORC1 has the ability to sense and integrate signals from a variety ofsources, including intracellular nutrients and secreted growth factors. The physiological and pathologicaactivation of mTORC1 results in downstream changes in cellular metabolism, with a shift from catabolic


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processes to anabolic biosynthetic processes. mTORC1 activity has been found in multiple species from yeastto mammals to contribute to aging, and mTORC1 is chronically activated in a variety of aging-related diseasesThrough unbiased genomic and metabolomic approaches, we have found that, in addition to its establishedroles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specificmetabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this mannermTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, andorganisms, including the de novo synthesis of proteins, lipids, and nucleic acids. In addition, we have recentlyuncovered a novel and surprising role for mTORC1 in controlling cellular protein and amino acid homeostasis

through the coordinated regulation of protein synthesis and degradation. This seemingly paradoxical functionof mTORC1 serves as both a quality control mechanism to handle the increase in misfolded proteins thataccompanies elevated rates of protein synthesis and as a means of maintaining adequate pools of intracellularamino acids to sustain new protein synthesis. The potential implications of these downstream functions ofmTORC1 in understanding the pathological manifestations of aging will be discussed.

Brendan Manning received his PhD from Yale University before joining the laboratory of Lewis Cantley aHarvard Medical School for his postdoctoral research. During his time in the Cantley laboratory, he discoveredthat the tuberous sclerosis complex tumor suppressors are the key molecular connection between the PI3Kand mTOR pathways, thereby linking a signaling pathway activated in the majority of human cancers to anutrient-sensing pathway that controls cell growth and metabolism. In 2004, Dr Manning joined the faculty othe then newly established Department of Genetics and Complex Diseases at the Harvard School of Public

Health, where he is now a professor and director of the PhD Program in the Biological Sciences in PublicHealth. Research in the Manning laboratory is focused on unraveling signaling networks that coordinatenutrient availability with metabolic responses and how dysregulation of such networks underlie aging andaging-related diseases.

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Proteostasis in Biology, Aging, and DiseaseRichard I. Morimoto, PhD, Northwestern UniversityThe proteostasis network (PN) is essential for the health of the proteome, optimal tissue function, and lifespanUnder ideal conditions, the PN prevents misfolding and aggregation that arises from genetic polymorphismserror-prone synthesis, and mutations, that are exacerbated by stress, aging, and disease. Critical componentsof the PN include the heat shock response (HSR), the unfolded protein responses, and antioxidant responsethat function in concert to protect the proteome against damage. Despite these protective networks, theexpression of 1/3rd of the human chaperome declines during brain aging and further in Alzheimer’sHuntington’s and Parkinson’s disease. Functional RNAi assays with C. elegans models of Ab and polyQexpression revealed that a core chaperome of 16 genes are essential to prevent misfolding and proteotoxicityIn C. elegans, this age-dependent decline in the HSR and other stress responses occurs abruptly uponreproductive maturity and appears to be regulated by epigenetic chromatin repressive marks that restricts theaccessibility of HSF-1 to the promoter regions of HS genes. At the organismal level, the transmission of stresssignals across tissues involves cell non-autonomous signaling from the environment to sensory neurons toregulate the HSR of somatic tissues, and by transcellular chaperone signaling to achieve balanced organismaexpression of chaperones between tissues expressing different levels of damaged proteins and altered levelsof chaperones. Orchestration of chaperone networks, therefore communicates the proteostatic state amongcells and surrounding tissues, to adjust the PN throughout development and adulthood and to prevent theconsequences of stress-induced proteotoxic damage.

Dr Morimoto is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for BiomedicaResearch in the Department of Molecular Biosciences at Northwestern University. He holds a B.S. from theUniversity of Illinois at Chicago, a PhD in Molecular Biology from The University of Chicago, and was apostdoctoral fellow at Harvard University. His research has been on the heat shock response, and the functionof molecular chaperones and the proteostasis network in biology to maintain cellular health and to respond tochallenges from environmental and physiological stress, aging and diseases of protein conformation. Thesestudies provide a molecular basis for the cellular and organismal stress response and its role in aging and age-associated degenerative diseases including neurodegeneration, metabolic diseases, and cancer. Morimoto


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has published over 250 papers and edited five books. Some of the academic honors and awards includeMERIT awards from the National Institutes of Health, elected membership in the American Association for the

Advance of Science and the American Academy of Arts and Sciences, Commandeur, Ordre des Palmes Académiques (France), and the Fyodor Lynen Medal of the German Society of Biochemistry and MoleculaBiology. He serves on Scientific Advisory Boards for the University of Heidelberg, RIKEN Brain ScienceInstitute, Roswell Park Cancer Institute, BioCity Turku, and the Max Planck Institute. He is a co-founder ofProteostasis Therapeutics, Inc. a Biotech in Cambridge, MA to discover small molecule therapeutics fordiseases of protein conformation.

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Role of Complement Cascade in Synapse Loss and Cognitive AgingBeth Stevens, PhD, Harvard Medical SchoolEarly synapse loss is a hallmark of aging and Alzheimers disease (AD) but what makes synapses vulnerableremains elusive. During development, synapse pruning is a normal and highly regulated process, required forproper brain wiring and synaptic connectivity. Recent work has revealed unexpected roles for proteins of theclassical complement cascade, an innate immune pathway, and microglia, immune cells that reside in theCNS, for elimination and refinement of synaptic connections in postnatal mouse brains. In developing brainC1q and C3 are deposited onto less active synapses for elimination by microglia that express CR3. Wehypothesized that similar mechanisms of synapse pruning may be involved to drive synapse loss in the agingbrain and in the early stages of AD pathogenesis. We found an early, region-specific upregulation and

deposition of complement (C1q) onto synapses in hippocampus and regions vulnerable to synapse loss, in twomouse models of Alzheimers disease. Preliminary results suggest genetic deletion of classical complementcascade components protect against early synapse loss and dysfunction in AD mouse models. Together ourresults suggest that aberrant reactivation of a normal developmental pruning pathway may work together tomediate early synapse loss in AD. . This study also has broad therapeutic implications for AD and other agedependent neurodegenerative diseases involving synaptic loss and dysfunction.

Beth Stevens received her PhD in Neuroscience in 2003 from the University of Maryland, College Park andcompleted her postdoctoral fellowship at the Stanford University School of Medicine in 2008. She is a recipienof several awards including: the Smith Family Award for Excellence in Biomedical Research, Dana Foundation

Award (Brain and Immunoimaging), Ellison Medical Foundation New Scholar in Aging award, John MerckScholar Program.

Session III. From Aging Biology to Drug Development for Neurodegenerative Disease

The Anti Aging Protein Klotho as a New Target for Treating Neurodegenerative DiseasesCarmela R. Abraham, PhD, Boston UniversityIn Alzheimers disease (AD), amyloid beta peptides (Ab) accumulate in the brain and are toxic to neurons andsynapses. Strategies either to interfere with Aβ formation or enhance its clearance have not succeeded inslowing the progression of the disease. We propose a novel approach intended to protect neurons from thetoxicity of Aβ and other age-related insults. Studying the anti-aging protein Klotho, our group has made fourimportant discoveries that have profound relevance to AD and likely other neurodegenerative disorders. Wefound that: 1) the levels of Klotho, which protects mice and humans from aging and disease, are much lower inthe aged healthy brain, in brains of AD patients and animal models of AD, 2) Klotho is able to rescuehippocampal neurons from Aβ and from oxidative stress and death induced by the excitotoxic amino acidglutamate, 3) a potentially novel molecular mechanism is responsible for the Klotho-induced neuroprotection,and 4) small molecule compounds that were developed from hits from a high throughput screen to enhanceKlotho expression, can mimic Klothos neuroprotective functions and rescue neurons from death. Furthermore,Klotho induces the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytesThis is particularly important for multiple sclerosis (MS) where there are plenty of OPCs around MS plaques,but where they fail to differentiate into mature myelin-forming cells. In summary, Klotho exhibitsneuroprotective properties to neurons and promotes differentiation of oligodendrocytes and, therefore, Klothoenhancing small molecule compounds that cross the blood-brain barrier could become novel therapeutics for

AD and MS.


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Carmela R. Abraham obtained her PhD in Neuroscience at Harvard University. She then moved to BostonUniversity School of Medicine where she is Professor of Biochemistry and Pharmacology & ExperimentalTherapeutics. Her laboratory studies the molecular mechanisms leading to normal brain aging and thepathological processes that culminate in Alzheimer’s disease (AD). By utilizing the rhesus monkey as a modefor understanding changes that occur during non-pathological aging her group discovered that the anti-agingprotein Klotho is downregulated with age. Klotho is also significantly reduced in the AD brain but its function inbrain was unknown. Dr Abraham and her colleagues embarked on elucidating Klotho’s role in the CNS. Thegroup discovered that Klotho protects neurons against various insults, including the neurotoxic amyloid beta

peptide, and oligodendrocytes, where Klotho induces their differentiation into myelinating cells. This isparticular important in multiple sclerosis (MS) where oligodendrocyte progenitor cells fail to mature andproduce myelin to repair demyelinated axons. As part of her translational research, Dr Abraham identifiedsmall molecule compounds that enhance Klotho expression and plans to test them in mouse models of AD andMS. Dr Abraham is the recipient of the Temple and Zenith awards from the Alzheimer’s Association.

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Stimulation of Macroautophagy with Small MoleculesHaung Yu, PhD, Columbia University

Autophagy is a major pathway for the clearance of redundant and aberrant proteins in cells, in addition toremoval of defective organelles, like mitochondria. In neurodegenerative diseases like Alzheimers disease

this process may be inefficient and this can be attributed to a reduction in the amount of autophagy or adownstream disruption of autophagic-lysosomal processing. Using models of tauopathy, an investigation ofsmall molecule activators of were investigated for their capacity to reduce phospho- and aggregated tau incells and organotypic brain slice cultures from tau transgenic models. This presentation will discuss use of anorganic molecule, trehalose, in addition to the identification of a lead compound and a series of modifiedstructures for their capacity to induce autophagy. This study also demonstrates that upregulation of autophagycan successfully ameliorate proteinopathy and reduce the physiological and behavioral deficits associated withtauopathy.

Dr Wai Haung (Ho) Yu received his PhD in Pharmacology from the University of Toronto and was a recipient oseveral awards including the Alzheimer Society of Canada Pre-doctoral award. Dr Yu went to NYU/NathanKline Institute on a Canadian Institutes of Health Research Postdoctoral Fellowship and was a ClinicalInstructor and then Assistant Professor prior to joining the Department of Pathology and Taub Institute forResearch on Alzheimer’s Disease and the Aging Brain at Columbia University (2006). Dr Yu’s researchinterests include the role of protein quality control in neurodegeneration examining the biological outcomes ofprotein homeostasis in neurons and the deleterious effects of failed degradation primarily of aggregate-proneproteins like tau and α-synuclein. Dr Yu’s lab is developing novel neuronal assays and identifying newmodulators of autophagic and lysosomal activity. Recent funding support includes NIH, Alzheimer DrugDiscovery Fund (ADDF), CurePSP, Alzheimer’s Association and BrightFocus. Dr Yu has served on ScientificReview Boards for the Veteran’s Administration, ADDF and W.G. Weston Foundation (Canada).

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A New Mitochondrial Target for Neurodegenerative DiseaseJerry Colca, PhD, Metabolic Solutions Development Company

Alzheimer’s disease and other neurodegenerative diseases have a contributing metabolic dysfunction thaincludes a progressive loss of mitochondrial function. This likely is a key reason while these diseases progresswith aging. It is also commonly observed that neurodegenerative diseases are associated with a phenomenonknown as insulin resistance, where growth factor signaling is impaired. Over the years, "insulin sensitizers"have shown positive results in preclinical models of neurodegeneration. We have recently found a previouslyunappreciated protein complex in the internal mitochondrial membrane that binds insulin sensitizing molecules.This complex, which we have termed mTOT (mitochondrial target of the thiazolidinediones), includes keycomponents of the mitochondrial pyruvate carrier as well as other important machinery that coordinatesoxidative metabolism. We have shown that treatment with a prototype mTOT modulator insulin sensitizer(MSDC-0160) maintains FDG-PET patterns patients with mild to moderate Alzheimer’s in a three month clinica


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trial, indicative of central effects. This presentation will summarize the results from this clinical trial and providean update on the understanding of this new mitochondrial target. It is possible that modulation of metabolismwith this pharmacology could provide a pathway to modify the course of neurodegenerative diseases.

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Jerry Colca, PhD, is a co-founder, part owner, and President/Chief Scientific Officer of Metabolic SolutionsDevelopment Company (MSDC; msdrx.com) in Kalamazoo, MI. Jerry has spent his professional career

studying the endocrine control of metabolism as relates to diabetes. He has a BS in Biology and MS and PhDin Physiology and Biochemistry from the University of Houston where he studied the regulation of secretion opancreatic hormones. His post doctoral training at Washington University concentrated on the biochemistry ofisolated pancreatic islets and the study of stimulus-secretion coupling in the control of metabolism. Jerry joinedthe Upjohn Company in 1984 to study to the mechanism of action of the thiazolidinediones and wasinstrumental in selection and development of pioglitazone hydrochloride (Actos®) as an anti-diabetic agentthrough Phase 2A clinical studies. The company formally known as Upjohn exited the insulin sensitizing field in1993. Jerry remained with the Upjohn Company through the mergers with Pharmacia, Monsanto-Searle, andPfizer until he retired from the merged company in 2005. During this time he was leader of diabetes discoveryteam in Kalamazoo, helped build a new diabetes discovery effort in Sweden after the merger with Pharmaciaand finally building a new targets discovery effort in St. Louis after the Pfizer merger. Jerry has been interestedin the mechanism of action of the insulin sensitizer TZDs from the early days of their discovery and especially

in the safety and pharmacology of pioglitazone. In January of 2006, Jerry co-founded MSDC with Dr RolKletzien to take advantage of their unique insight into these molecules. The company has now grown to havetwo compounds in clinical trials and is making significant progress into understanding the molecularmechanisms of the insulin sensitizers. These efforts have identified a novel mitochondrial target through whichnew insulin sensitizers coordinate a pharmacology that can modify diseases of metabolic dysfunction.

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Targeting Neuroinflammation by Inhibiting Glial Cell Cytokine OverproductionD. Martin Watterson, PhD, Northwestern University Feinberg School of MedicinePerturbation of homeostasis mechanisms critical to synaptic function is a component of pathology progressionin diverse neurodegenerative diseases and the neurologic sequelae to brain injury. Stressor inducedupregulation of proinflammatory cytokine production and the associated synaptic dysfunction is considered a

key player in these mechanisms due to disruption of the glia-neuronal axis. Attenuation of the pathologyprogression offers the potential of disease modifying therapeutic intervention. We have applied a CNS focuseddrug discovery engine to the development of novel small molecule candidates that attenuate this injuriousproinflammatory cytokine overproduction and the associated synaptic dysfunction. The discovery engine is arecursive, biology-driven chemistry platform that leverages small molecule pharmacoinformatics at the designand synthesis planning stage, and includes early pharmacological parsing of the novel synthesizedcompounds. The presentation will cover two distinct classes of drug candidates emerging from the applicationof this discovery engine. One class is a preclinical deliverable at the IND enabling stage that uses the popularsingle molecular target approach and employs high resolution co-crystallography and pharmacoinformaticsbased on small molecule CNS drugs. The second class that is in clinical trials stage emerged from theclassical and more unbiased phenotypic approach with heavy dependence on pharmacoinformatics based onsmall molecule CNS drugs and re-utilization of validated CNS drug scaffolds. Both classes of compounds are

orally active, brain-penetrant, small molecules that are selective, efficacious and safe in preclinical animamodels of Alzheimer’s disease. Our data suggest that selective targeting of the dysregulated cytokineresponse, a component of the neuroinflammation that contributes to synaptic dysfunction, is an attractivetherapeutic strategy for neurodegenerative disorders such as Alzheimer’s disease.

Dr Watterson holds the G.D.Searle Chair Professorship at Northwestern University where he founded asuccessful academic drug discovery program that brought CNS drug candidates to preclinical and clinicadevelopment. Administratively, he has served as a Department Chair, University Center Director andCurriculum Co-Director. His academic service record is complemented by commercial experience with smalbusiness start-ups, board of director service and pharmaceutical industry consulting. Dr Watterson directs an


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advisory group that assists companies, government agencies and research institutes in the processes of drugdiscovery and translation of basic science progress into clinically relevant deliverables. His previous academicappointments include faculty positions at The Rockefeller University, where he was an Andrew Mellon Fellow,and at Vanderbilt University Medical Center, where he was Professor of Pharmacology and an Investigator inthe Howard Hughes Medical Institute.

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Biological and Chemical Approaches to Adapt Proteostasis to Ameliorate Protein AggregationDiseasesJeffrey W. Kelly, PhD, Scripps Research InstituteThe cellular protein homeostasis, or proteostasis network, regulates proteome function by controlling ribosomaprotein synthesis, chaperone and enzyme mediated protein folding, protein trafficking, protein degradation andthe like. Stress responsive signaling pathways match proteostasis network capacity with demand in eachsubcellular compartment to maintain cellular homeostasis. The beginning of the seminar will focus on how theproteostasis network can be adapted through unfolded protein response arm-selective signaling to alleviategain-of-toxic-function diseases where excessive secretion of misfolding and aggregation of proteins leads tothe amyloid diseases. The second part of the seminar will focus on a chemical strategy to achieve proteinhomeostasis, wherein small molecule kinetic stabilizers produced by structure-based drug design areemployed to halt the progression of peripheral neuropathy in the human disease familial amyloid

polyneuropathy linked to transthyretin amyloidogenesis. I will explain how delineating the molecularmechanism of transthyretin aggregation linked to pathology led to a regulatory agency approved drug. Sincethis is the first pharmacologic evidence supporting the amyloid hypothesis, the notion that protein aggregationcauses degeneration of the heart and the nervous system, the last part of the seminar will focus on what wehave learned about the etiology of these diseases vis-à-vis a successful clinical trial.

Jeffery W. Kelly, PhD, is the Lita Annenberg Hazen Professor of Chemistry in the Department of Chemistry anthe Chairman of the Department of Molecular and Experimental Medicine at the Scripps Research InstituteKelly also served as Vice President of Academic Affairs and Dean of Graduate Studies at Scripps for nearly decade. His research is focused on uncovering protein folding principles and on understanding the etiology oprotein misfolding and/or aggregation diseases and using this information to develop novel therapeutstrategies. He has 290+ publications and has received several awards, including The American ChemicaSociety Ralph F. Hirschmann Award in Peptide Chemistry (2012), The Biopolymers Murray Goodman MemoriaPrize (2012), The Protein Society Emil Thomas Kaiser Award (2011), The American Peptide Society RaMakineni Lectureship (Award; 2011), The American Peptide Society Vincent du Vigneaud Award (2008), Th

American Chemical Society Arthur C. Cope Scholar Award (2001), State University of New York at Fredoni Alumni Distinguished Achievement Award (2000), The Protein Society–Dupont Young Investigator Awar(1999) and The Biophysical Society National Lecturer (Award;1999). Kelly cofounded FoldRx Pharmaceuticalbased on his discovery of Tafamidis–approved by the European Medicines Agency in 2011 and the Japanesauthorities in 2013 to treat familial amyloid polyneuropathy. This first-in-class drug is the first pharmacologiagent that halts neurodegeneration in a human amyloid disease. Tafamidis or Vyndaqel also provides the firspharmacologic evidence that the process of amyloidogenesis causes the degeneration of post-mitotic tissue. Halso cofounded Proteostasis Therapeutics, a company using small molecules to alter the protein homeostasinetwork to ameliorate several aggregation-associated degenerative diseases (e.g. Parkinsons) as well as lossof-function diseases (Cystic Fibrosis). In 2012 Kelly Cofounded Misfolding Diagnostics, Inc., a San Diegcompany focusing on the early diagnosis of degenerative diseases.


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Biology of Aging Program-05.9.14