Together we Drive the Future

Neurodegenerative Diseases Research & Development

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Day 1 – Monday, September 12, 2016
7:00 Continental Breakfast & Registration
7:55  Opening Remarks
I. Novel Therapeutics & Approaches in Alzheimer’s Disease
Moderator: Michael EganAssociate Vice President in Clinical NeuroscienceMerck&Co
8:00   Antibody-Mediated Targeting of Tau in vivo Does not Require Effector Function and Microglial Engagement
  Gai Ayalon
8:25 Forebrain Depletion of Rheb GTPase Elicits Working and Spatial Memory Deficits in Mice
  Srinivasa Subramaniam
Associate Professor, Department of Neuroscience
The Scripps Research Institute
  The precise molecular and cellular events responsible for age-dependent cognitive dysfunctions remain unclear. We report that small guanine nucleotide-binding protein Rheb (ras homolog enriched in brain), an activator of mammalian target of rapamycin (mTOR), regulates memory functions in mice. Conditional depletion of Rheb selectively in the forebrain of mice obtained from crossing Rhebflox/flox and CamKIICre results in spontaneous signs of age-related memory loss, i.e., working and spatial memory deficits (T-maze, Morris water maze) without affecting locomotor (open-field test), psychiatric (elevated plus maze), or contextual fear conditioning functions. Partial depletion of Rheb in forebrain was sufficient to elicit memory defects with little effect on the neuronal size, cortical thickness or mTOR activity. Rheb depletion, however, increased the levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein elevated in Alzheimer disease, consistent with our previous report (Shahani, et al., 2014). Overall, our study demonstrates that forebrain Rheb promotes aging-associated cognitive defects.Thus, targeting the Rheb pathway may provide therapeutic potentials for aging and/or AD-associated memory deficits.
8:50 A Cellular Model of Spontaneous Tau Hyperphosphorylation and Aggregation
  Joel Schachter
Principal Scientist, Neuroscience Molecular Discovery
  Tau hyperphosphorylation and tau aggregation are principal aspects of the neurofibrillary pathology associated with Alzheimer’s disease (AD) and other neurodegenerative Tauopathies. Small soluble tau oligomers, as opposed to large insoluble tau filaments, are now considered to play a causal role in the neurodegenerative process. Despite prior demonstrations of phosphorylated tau aggregation in transgenic animals and filament formation of purified tau in vitro, a detailed understanding of cellular mechanisms associated with tau pathology has been limited by the difficulty in establishing cellular model systems that display hyperphosphorylation and aggregation of full length wild type tau. We describe a novel cellular model of tau expression using inducible tau constructs that are prone to spontaneous aggregation in situ. The tau aggregates formed in this cell model are PBS-soluble oligomers that are stable to dilution, heat, and detergents. Further evaluation reveals that the tau oligomers are hyperphosphorylated at several AD-relevant epitopes and are prone to multiple proteolytic cleavages. The audience for this presentation will gain an understanding of how soluble tau oligomers can be generated and monitored in a cellular model system and how such a system can be used to study tau pathobiology and perform drug discovery for the treatment of neurodegenerative Tauopathies.
9:15  Development of BACE Inhibitors for Alzheimer’s Disease
  Michael Egan
Associate Vice President in Clinical Neuroscience

The discovery of potent BACE inhibitors is changing the landscape of clinical research in Alzheimer’s disease (AD). In contrast to prior anti amyloid candidates, BACE inhibitors have been demonstrated to substantially (>80%) lower production in the brain of Abeta, the primary constituent of amyloid plaque. BACE inhibitors will therefore provide an opportunity to robustly test the amyloid hypothesis.

A key issue in the development of BACE inhibitors is how early in the disease process treatment should be initiated. Trials are currently underway that will evaluate efficacy at later stages of disease, including preclinical, prodromal and mild-moderate AD. Subjects in these trials have relatively high levels of brain amyloid, as assessed by PET scans. Disease progression in these stages, however, has been more closely linked in some studies to tau pathology than brain amyloid load. Furthermore, studies using transgenic mouse models h that, in the context of high amyloid load, progression of tau pathology may propagate in part via cell to cell transmission. This raises the possibility that initiating BACE inhibitors early in the disease process, prior to the development of high amyloid load, could be an optimal strategy for slowing tau pathology and disease progression. Such trials have not yet been attempted and will require new approaches in clinical trial methodology.

9:40   Functional Modeling of the Human Cerebrovasculature
  Cheryl Wellington
Professor, Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health
University of British Columbia
  Developing next-generation models to define how Alzheimer’s Disease (AD) and vascular risk factors interact is a key strategic research priority for dementia. In healthy people, two of the three ways by which neuronally produced Aβ is cleared from the brain involve the cerebral vessels. As we age, this process fails, and Aβ accumulates in cerebral vessels and triggers a vascular inflammatory response that exacerbates cognitive decline. To provide an innovative platform to study human vascular contributions to dementia, we used tissue engineering methods to cultivate 3-dimensional functional cerebral blood vessels consisting of primary human endothelial cells (EC), primary human smooth muscle cells (SMC), and primary human astrocytes, all cultured in a bioreactor that mimics blood flow through the vessel lumen. Engineered cerebral vessels have a tight EC barrier including expression of blood brain barrier transporters, preserved regulation of astrocyte apoE secretion, and EC functions including nitric oxide (NO) production and reaction to inflammatory stimuli including A? as measured by monocyte adhesion. Aβ injected into the graft chamber (the “brain side”) accumulates in the vessel and can also be detected in the circulation chamber (the “blood side”). Our experimental platform offers an innovative method to investigate human cerebrovascular functions, including regulation of and transport across the blood brain barrier, drug development, blood tests that offer a functional readout of the cerebrovascular response and the potential to personalized medicine.
10:05 Morning Networking Break
10:45  Exosome Pathway as a New Therapeutic Target of Tau Propagation in Alzheimer’s Disease
  Tsuneya Ikezu
Professor, Departments of Pharmacology & Experimental Therapeutics and Neurology
Boston University School of Medicine
  The neurofibrillary tangle is a pathological hallmark of Alzheimer’s disease (AD) and primarily consists of hyper-phosphorylated tau protein (pTau). pTau first appears in the entorhinal cortex in the presymptomatic stage, then gradually disseminates to the hippocampal region around the onset of clinical symptoms of AD. Halting this tau spread in the asympomatic stage is a promising therapeutic approach for AD. The exosome is a small vesicle of 50-100 nm in diameter, enriched in ceramide, and is suggested to contain neuropathogenic proteins, such as tau protein. A growing body of evidence suggests that microglia contribute to tauopathy-related pathogenesis in both human and animal models. We hypothesize that microglia transduce tau aggregates into nearby neuronal cells via exosomal secretion, and that inhibition of the exosome synthesis or secretory pathway reduces tau dissemination. To develop new mouse model, adeno-associated virus expressing FTDP-17-linked mutation of tau protein was stereotaxically injected into the entorhinal cortical region of C57BL/6 mice. We found that human tau propagate from entorhinal cortical neurons to dentate granular cells after AAV injection, and that this propagation is sensitive to the inhibition of exosome synthesis or microglial depletion. We also found that tau-containing exosomes isolated from microglia efficiently transduce tau protein to neurons in vitro and in vivo. These results demonstrate that exosome secretion from microglia play a significant role in propagation of tau protein, and that targeting this pathway may be beneficial in ameliorating the disease progression.
II. Advances in Parkinson’s Disease Research & Therapeutics
Moderator: Gai Ayalon, Scientist, Genentech
11:10  Rare Diseases as a New Paradigm for Drug Discovery: Lessons from the Gaucher-Parkinson’s link
  Pablo Sardi
R&D Director, Neuroscience
Sanofi Genzyme
  Mutations in GBA, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson’s disease (PD). Recent studies have also demonstrated that genetic variation in GBA can impact the progression of PD. Patients harboring mutations in GBA present higher prevalence and severity of motor and non-motor symptoms. However, the precise mechanisms by which mutations in GBA increase PD risk and exacerbate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. A Gaucher-related synucleinopathy mouse model (GbaD409V/D409V) was treated with an orally available brain-penetrant GCS inhibitor for 8 months. This intervention prevented CNS substrate lipid accumulation. Most notably, treatment with the GCS inhibitor slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin and tau, and improved the associated memory deficits. The effects of the GCS inhibitor were also studied in a mouse model overexpressing α-synuclein, PrP-A53T- SNCA, and harboring wild type alleles of GBA. Treatment of PrP-A53T-SNCA mice with GCS inhibitor for 6.5 months reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. Collectively, the data indicate that inhibition of GCS can modulate processing of α-synuclein, thereby reducing the progression of synucleinopathies. The present study provides supporting evidence for the clinical development of brain-penetrant GCS inhibitors in GBA-PD and other synucleinopathies.
11:35  Autophagy and Lysosomes in Parkinson’s Disease
  Baris Bingol
Scientist, Neuroscience
  Parkinson’s disease (PD) is a common neurodegenerative movement disorder characterized by death of dopaminergic neurons, and by presence of α-synuclein- and ubiquitin-rich protein inclusions in remaining neurons. The presence of these inclusions in PD suggests that defective protein handling contributes to the pathogenesis of the disease. Autophagy is a central homeostasis pathway that functions to target damaged proteins and organelles to lysosomal degradation. A role for defective autophagy and lysosomal degradation in PD is supported by the recent human genetics and pathology data. It is thought that the defective lysosomal degradation impair clearance of long-lived proteins, such as α-synuclein, and removal of damaged organelles, such as mitochondria. In this presentation, I will summarize the data that point to a role of lysosomal protein degradation in PD, discuss how defects in lysosomes can lead to neuronal death, and highlight novel targets that emerged from the autophagy and lysosomal biology.
12:00 Lunch on Your Own
1:30  SER-214 – A Once-weekly Injection That Provides Continuous Drug Delivery for Parkinson’s Disease 
  Randall Moreadith
President and CEO
Serina Therapeutics
  SER-214 is a once-weekly subcutaneous injection that can be delivered in a standard insulin syringe for the treatment of Parkinson’s disease. Robust animal models in Parkinson’s disease demonstrated the attached dopamine agonist, rotigotine, could be delivered continuously following a single weekly injection with prompt reversal of Parkinsonian deficits. SER-214 has advanced into Phase I in patients with Parkinson’s disease and the results of the initial findings will be presented. 
1:55  Why are Melanoma and Parkinson’s Disease Linked?: Role of MC1R?
  Xiqun Chen
Assistant Professor of Neurology
Harvard Medical School
  Patients with Parkinson’s disease (PD), one of the most common neurodegenerative diseases, generally have reduced risk of developing almost all types of cancer, with one notable exception – melanoma, a malignant tumor of melanin-producing cells in skin. A large number of epidemiological studies have reported that individuals with PD are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing PD. Although well documented since the 1970s, mechanisms underlying this association remain largely unknown. The talk will highlight recent findings by our interdisciplinary collaborative team including leading epidemiologists, melanoma specialists, and cancer geneticists.
2:20 Metabotropic glutamate receptor 4 positive allosteric modulators for Parkinson’s disease: impact of receptor heterodimerization
  Colleen Niswender
Research Associate Professor of Pharmacology;
Director of Molecular Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery
Vanderbilt University

Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy, 6-hydroxydopamine-induced lesion, and MPTP-treated nonhuman primates.

Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu4 are co-expressed, whereas other compounds potentiate mGlu4 responses regardless of the presence of mGlu2. This translates into distinctions in modulation of synaptic responses and generates the hypothesis that PAMs with activity at heteromeric receptors may show distinctions in their antiparkinsonian profile versus PAMs that only potentiate mGlu4 homomers. Using Complemented Donor Acceptor Resonance Energy Transfer (CODA-RET) technology to specifically isolate responses emanating from an mGlu2/4 heteromer, we find that the mGlu4 PAM VU0418506 does not potentiate agonist-induced activity when mGlu2 and mGlu4 are heterodimerized. This is contrast to another PAM, Lu AF21934, which does potentiate agonist-induced CODA-RET responses at mGlu2/4 heteromers. Both of these compounds, regardless of potentiation profile, show antiparkinsonian activity in vivo, suggesting that potentiation of mGlu4 homomeric receptors underlies the antiparkinsonian activity of mGlu4 PAMs. Additionally, lack of activity at mGlu4 heteromeric receptors may suggest enhanced selectivity of mGlu4 homomeric PAMs, which may improve safety profiles.

This work was supported by funding from the NIH, the Michael J. Fox Foundation, and Bristol-MyersSquibb.

2:45 Afternoon Networking Break
III. Rare and Orphan CNS Disorders
Moderator: Srinivasa Subramaniam, Associate Professor, Department of Neuroscience, The Scripps Research Institute
3:30  Huntington’s Disease: From Pathogenesis to Therapeutics
  Wenzhen Duan
Associate Professor, Psychiatry
Johns Hopkins University
  Huntington’s disease is a rare hereditary degenerative disease with a wide variety of symptoms that encompass movement, cognition, and behavior. A number of clinical trials targeting these metabolic consequences have failed to produce a single effective therapy, although clinical trials continue. New strategies targeting the protein at the level of transcription, translation, and posttranslational modification engender new hope that a successful strategy will emerge, but there is much work ahead, because the precise pathophysiological mechanisms of neurodegeneration are complex and multifactorial. Preclinical studies have identified a plethora of potential targets for disease modification. Great opportunity exists to identify disease modifying therapies in HD because it is a monogenic illness, with a known gene and gene product, and a number of genetic models, and because one may identify gene carriers long before clinical symptoms begin. Our research focuses on identifying and validating potential therapeutic targets, and developing small molecule agents and biomarkers for this devastating neurological disorder. 
3:55 Developing SMRT Drugs for Treating Nonsense Mutations; A New Model, Single Drugs for Groups of Genetic Diseases
  Richard Gatti
Professor in Residence, Department of Human Genetics
  We are developing drugs that correct the read-through of premature STOP codons (i.e., nonsense mutations). Such mutations occur in roughly one-third of most the 8000 known genetic disorders. The work began 15 years ago, using Ataxia-telangiectasia (A-T) as our research model. A-T is a rare autosomal recessive disorder that results from the absence of the hierarchical serine/threonine PI3 protein kinase, ATM, and its subsequent failure to phosphorylate >700 downstream substrates, which play critical roles in the recognition and repair of double strand DNA breaks and cell replication. A-T manifests primarily as a progressive cerebellar impairment of fine motor movements, increased susceptibility to cancer, characteristic chromosomal translocations, and hypersensitivity to ionizing radiation. In 1988, the gene responsible for A-T was located by our group on chromosome 11q22-23 and, seven years later, a single causative gene was cloned. Once the worldwide spectrum of ATM mutations had been clearly defined, various molecular genetic approaches to mutation-targeted therapy were initiated. These efforts are nearing fruition through the development of small molecule read through (SMRT) chemicals, which act upon nonsense mutations to alter the fidelity of mRNA translation at premature termination codons. In 2005, using a high throughput screening assay that we developed, four novel groups of compounds (Structure-Activity Related groups) were selected and further characterized (RTC13, RTC14, GJ071, and GJ072) from 70,000 chemicals. Of these ~140 derivative compounds were designed, synthesized and tested for readthrough. We presently have over 20 active SMRT chemicals with drug-like properties. All of these chemicals read through all three STOP codons (TAG, TGA, TAA). Some restore functional protein in models of A-T, DMD mice, epidermolysis bullosum, xeroderma pigmentosum, and congenital blindness (LCA16 Kir 7.1). LC-MS detects several of them in the cerebellum, the primary target organ for treating A-T. Some have been screened for ADMET, cytotoxicity, and are generally well-tolerated in mice. We are presently trying to de-risk future SMRT drug development by establishing a mouse model that will document in vivo correction of nonsense mutations in the atm gene and improving the throughput of measurements of ATM protein and function at levels between 5% and 40% of normal, the targeted therapeutic zone. We have come to appreciate that perhaps single drugs may suffice for treating groups of patients with many different genetic diseases, based not on the gene that is mutated but on the pathogenesis of the type of mutation causing each patient’s disease. This new insight could produce a sea-change in treating genetic disorders, most of which remain without an effective treatment. Furthermore, this approach would dramatically reduce the number of candidate drugs that need to be developed and FDA approved for the 8000 genetic disorders.
4:20  Precision Medicine 2016: Personalized Medicine using Stem Cell Biology
  Stephen Chang
Senior Vice President, Research and Development
New York Stem Cell Foundation
  The genetic variation in the human population is most evident by the phenotypic distribution of the human species. Yet sequence analysis reveals that our genetic similarity through gene organization is remarkable. Given the degree of similarity of genetic sequence, tools such as gene editing and induced pluripotent stem cells are essential in our understanding of variation and disease causing mutations. At NYSCF we have developed unique capabilities in which large populations of people can be studied using personalized stem cells. This system Global Stem Cell Array TM is a system to derive, differentiate and edit stem cells with parallel and high output. We will discuss this system and how we are using it to advance cures for rare diseases, Parkinson’s and Alzheimer’s.
4:45 Preserving Neuromuscular Synapses in ALS
  Steven Burden
Professor and Coordinator for the Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine
NYU Medical School
  ALS is a devastating disease, progressing from detachment of motor nerve terminals to paralytic, lethal respiratory failure within several years of diagnosis. The mechanisms responsible for axon withdrawal are poorly understood, but the loss of neuromuscular synapses is sufficient to cause paralysis and therefore central to disease. Although the subsequent loss of motor neurons has received more attention, preventing motor neuron cell death without preserving neuromuscular synapses cannot stop disease progression. Skeletal muscles provide retrograde signals that promote the differentiation and stabilization of motor nerve terminals. The production of retrograde signals depends upon a synaptic receptor tyrosine kinase, termed MuSK. We tested whether increasing retrograde signaling in a mouse model of ALS, SOD1G93A transgenic mice, would stabilize neuromuscular synapses and ameliorate disease symptoms. We found that increasing MuSK expression reduced muscle denervation in SOD1G93A mice, improving muscle function for over one month, suggesting a novel therapeutic approach to slow the steady decline in motor function in familial and sporadic forms of ALS. A previous study described an antibody to MuSK, which stimulates MuSK in cultured myotubes. We found that a single injection of this agonist antibody in SOD1G93A mice reduced denervation and increased innervation for one month. Thus, increasing MuSK activity, after denervation and disease symptoms become evident in ALS mice, slows synaptic loss. We are currently studying whether the agonist antibody improves motor function and whether chronic dosing with the agonist antibody preserves synapses, improves motor performance and prolongs longevity of SOD1G93A mutant mice.
5:10 EDS for the Treatment of Ataxia Telangiectasia
  Luca Benatti
Chief Executive Officer
EryDel S.p.A

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder caused by mutation in the ATM gene, with onset in the first years of life. Neurological degeneration is the major contributor to the severe outcome of the disease. No established therapy is currently available, and current treatments are symptomatic and supportive only. The EryDex System (EDS) is used to load dexamethasone sodium phosphate (DSP) into autologous erythrocytes, creating the EDS end product (EDS-EP), which is infused once per month into the patient. This delivery system enables administering dexamethasone at stable low systemic levels over an extended period of time.

In a 6-months Phase II trial in 22 AT patients the EDS was shown to be effective in improving key neurological symptoms of the disease without evidence of typical steroid side effects. Long term benefit of EDS treatment in AT has been recently supported by observation from a compassionate use (Leuzzi et al 2015). The EDS received Orphan Drug designation for the treatment of AT both from the FDA and the EMA. Following consultation with key regulatory agencies, including FDA and EMA, EryDel is about to initiate a multicenter multinational Phase III registration trial with EDS in AT.

  [Short Oral Presentation from Exemplary Submitted Abstracts]
5:35 Characterization of a Translatable SNCA-based in vitro Screen for Identification of Disease-modifying Therapies for Parkinson’s Disease
  Dr. Jemma Gatliff
Keregan Therapeutics
  PD (Parkinson’s disease) is the second most common neurodegenerative disorder and there are no disease modifying treatments currently marketed. Despite major advances in our understanding of the disease, significant barriers during early stage R&D remain, including a lack of translatable disease models. SNCA (alpha synuclein) is a critical factor that contributes to the molecular onset and progression of disease in a majority of PD cases (sporadic and inherited). In normal physiology SNCA is a soluble monomer that regulates neurotransmitter release, synaptic plasticity and intracellular trafficking. In disease, it forms various oligomeric species that can be toxic or benign. Several missense point mutations, and duplications/triplications, have been identified in the SNCA gene with varying penetrance. In terms of disease model SNCA whole locus multiplications are the most relevant to sporadic patients but penetrance can be as low as 30%. Using recombinant protein fails to display robust neurodegeneration, making it difficult to establish a reproducible disease model. The point mutation at base 152, codon 51, causing a glycine to aspartic acid amino acid change (G51D), was identified in 2013. It is rare but causes a fully penetrant form of the disease that is clinically characterized by early onset and rapid progression. Here we describe a high-throughput phenotypic screen that models PD progression utilizing differentiated SH-SY5Y neurons harboring a Tet-One doxycycline (DOX)-inducible G51D-SNCA stable transgene. When expressed, the mutant protein aggregates and accumulates in the cell causing a strong phenotype from 4 days post induction. Here we present a comprehensive profile of the G51D SH-SY5Y cell PD model. Key read-outs associated with PD were investigated including i) SNCA oligomerization ii) neuronal morphology, iii) proteasome activity, iv) autophagy, v) mitochondrial function and vi) REDOX stress. This screen has the advantage of being inexpensive, rapid and yielding reproducible and clinically relevant data. It may be widely adopted to screen existing drug libraries to accelerate identification of disease-modifying drug candidates for PD.
5:45 Neurodegenerative Brain Repair is Induced by Running Through VGF-Mediated Oligodendrogenesis
  Matias Alvarez-Saavedra
Postdoctoral Fellow
Howard Hughes Medical Institute
  The protective effect of exercise is recognized as a means to enhance cognitive function and slow neurodegenerative disease progression and disability, yet the molecular mechanisms remain largely unknown. Here, we show that long-term survival and motor dysfunction in mice with progressive cerebellar ataxia caused by the conditional inactivation of the Snf2h gene (Snf2h cKO) can be rescued by voluntary exercise. Running induced oligodendrogenesis in the cerebellum and inferior olive that resulted in a striking increase in cerebellar myelination. Comparative RNA-seq analysis highlighted an upregulation of genes involved in activity-dependent synaptic transmission, neurotransmitter biosysnthesis and neuropeptide precursors that correlated with increased dendritic arborization and rescue of motor deficits. These beneficial changes were dependent on continued exercise, as removal of the exercise wheel resulted in diminished performance and a poorer prognosis. Further experiments with the VGF growth factor demonstrated that VGF neuropeptides could promote oligodendrogenesis in vitro, while Snf2h cKO mice treated with VGF-encoding adenoviruses showed an increase in cerebellar myelination and prolonged survival. Together, these results provide insight into an endogenous mechanism of brain repair and how VGF neuropeptide delivery could represent a therapeutic strategy for cerebellar ataxia and other pathologies of the central nervous system.
5:55 Evening Reception & Poster Session
Day 2 – Tuesday, September 13, 2016
7:00 Continental Breakfast
IV. Neuroinflammation Across CNS Disorders
Moderator: Robyn Klein, Professor, Internal Medicine, Infectious Diseases, Neuroscience, Washington University
8:00   Neuroimmunology Meets Neurodegeneration in Biogen’s Research Programs
  biogen Richard Ransohoff
Vice President & Senior Research Fellow, Neuroimmunology
8:25 Virus Versus Host: Post-Infectious Cognitive Dysfunction After Viral Encephalitis
  Robyn Klein
Professor, Internal Medicine, Infectious Diseases, Neuroscience
Washington University
  Greater than 50% of patients who survive neuroinvasive West Nile virus (WNV), a mosquito-borne, positive-sense strand flavivirus, exhibit cognitive sequelae including memory impairments which may last several years. Early diagnosis and high survival rates from WNV neuroinvasive disease (WNND) (>90%) have led to hundreds to thousands of cases of WNV-mediated neurologic impairment accruing annually, yet underlying mechanisms responsible for these impairments have not been investigated. Studies in humans and rodents indicate that neurons within cortical structures such as the hippocampus are highly targeted during WNV infection. The hippocampus is essential for spatial and contextual memory formation via a trisynaptic circuit involving the entorhinal cortex, dentate gyrus, CA3, and CA1 regions of the hippocampal formation. Damage to hippocampal neurons, their synaptic connections, or alterations in expression of critical gene pathways could restrict proper spatial memory formation or recall. We have established a novel murine model of recovery from WNND in which intracranial inoculation of a mutant WNV (WNV-NS5-E218A) leads to rates of survival and cognitive dysfunction that mirror human WNND. WNV-NS5-E218A-recovered mice exhibit impaired spatial learning and persistently phagocytic microglia without significant loss of hippocampal neurons or brain volume. Whole transcriptome analysis of hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning revealed increased expression of genes known to drive synaptic remodeling by microglia, including the classical complement pathway and phagocytosis. C1qA, which initiates the classical complement cascade, was found to be significantly upregulated and localized to microglia/macrophages, infected neurons, and presynaptic terminals during WNND. Indeed, quantitative immunohistochemistry studies uncovered a WNV-mediated loss of hippocampal CA3 presynaptic terminals in both mice and human WNND post-mortem samples. Further confocal microscopy studies revealed significantly more engulfment of presynaptic terminals by microglia/macrophages during acute and recovery stages following WNND. Importantly, mice with fewer microglia (IL-34-/-) or mice deficient in complement component C3 (C3-/-) or complement 3a receptor (C3aR-/-) were protected from WNV-induced presynaptic terminal loss. Our study provides a novel murine model of WNV-induced spatial memory impairment, shows that viral infection of adult neurons induces complement-mediated elimination of synaptic terminals, and identifies a potential mechanism underlying neurocognitive impairments experienced by patients recovering from WNND.
8:50 Inflammation and Traumatic Brain Injury: Strategies for Treatment and Diagnosis
  Susanna Rosi
Associate Professor, Departments of Physical Therapy & Rehabilitation Science and Neurological Surgery
University of California, San Francisco
V. Biomarkers: Translation from Discovery to Clinical
Moderator: Susanna Rosi, Associate Professor, Departments of Physical Therapy & Rehabilitation Science and Neurological Surgery, University of California, San Francisco
9:15 Biomarkers and Novel Pain Targets
  Mark Corrigan
Board Member
Quartet Medicine

Clinical research in pain has been fraught with failures and relied on subjective outcomes. This talk will cover the discovery of a novel non-opiate drug target for the treatment of pain and the associated translational medicine approach to identify a biomarker of target engagement and possibly associate with clinical outcome. Benefits

  1. Identification of novel pain targets
  2. Command of the biological pathway involved
  3. Understanding of the biomarker generation
  4. The utility of using a biomarker approach in pain research
9:40 New Frontiers in CNS Biomarkers Utilizing Single Molecule Array (Simoa) Technology
  Andreas Jeromin
Chief Medical Officer (consulting)
Quanterix Corp

The single molecule array (Simoa) has revolutionized the detection of low abundance CNS biomarkers in blood, but also cerebrospinal fluid (CSF). The presentation will describe the science underlying Simoa and describe selected case studies of the detection of tau in Alzheimer’s Disease and neurofilament light chain (NFL) in neurological disease.
The Simoa assays are run on an automated analyzer, HD-1, and can also be multiplexed. The platform is also open, allowing for an easy transfer of existing assays onto Simoa.

In summary, Simoa provides a unique toolbox of CNS biomarkers for use in diagnosis, prognosis and drug development.

10:05 Morning Networking Break
VI. Advances in Genetics and Systems Biology
Moderator: Lisa Ellerby, Associate Professor, Buck Institute
10:45 Using Huntington’s Disease with Induced Pluripotent Stem Cells to Identify Novel
  Lisa Ellerby
Associate Professor
Buck Institute

Huntington’s disease (HD) is a debilitating, inherited neurological disorder characterized by chorea, psychological changes, and cognitive decline leading to dementia. HD is caused by a CAG expansion coding for the polyglutamine located in the N-terminal region of the huntingtin protein (HTT). We have utilized induced pluripotent stem cells (iPSCs) derived from Huntington’s disease patients (HD iPSCs) as a human model of HD and determined that the disease phenotypes only manifest in the differentiated neural stem cell (NSC) fate, not in iPSCs. To understand the molecular basis for the CAG repeat expansion dependent disease phenotypes in NSCs, we performed transcriptomic analysis of HD iPSCs and HD NSCs compared to isogenic controls using RNA-Seq. Differential gene expression and pathway analysis pointed to TGF-??as the top dysregulated pathway. Using data driven gene coexpression network analysis, we identified seven distinct coexpression modules, and focused on two that were correlated with changes in gene expression in NSC due to the CAG expansion. Strikingly, our HD NSC model revealed the dysregulation of genes involved in neuronal development and the formation of the dorsal striatum in HD. Further, the striatal specific and neuronal networks disrupted could be modulated to correct HD phenotypes and provide novel therapeutic targets for HD.

The funding for this research was provided by CHDI (L.M.E.), NIH T32 AG000266 (L.M.E., R.N.O., K.R.) and F32 NS080551 (R.N.O.) training grants.

11:10 GWAS, eQTL and Regulatory Annotation Data Implicate Myeloid Cell Function (Efferocytosis) and Myeloid Transcription Factor SPI1/PU.1 in the Etiology of Alzheimer’s Disease
  Edoardo Marcora
Associate Professor, Neuroscience & Genetics and Genomic Sciences
Icahn School of Medicine at Mount Sinai
  Genome-wide association studies (GWAS) have been very successful in generating lists of trait- or disease-associated SNPs. However, these lists usually yield little information about the genes, pathways and cell types that these (mostly non-coding) SNPs affect. Therefore, the translation of GWAS findings into an understanding of disease biology and the identification of disease-modifying drug targets has proven to be difficult. In this study, we have used the International Genomics of Alzheimer’s Project (IGAP) GWAS dataset for late-onset Alzheimer’s disease (AD), in combination with other publicly available datasets of cell-type specific expression quantitative trait loci (eQTLs) and regulatory features, to develop mechanistic hypotheses of the impact of common, non-coding variants on AD susceptibility and age-at-onset. First, we showed that AD GWAS SNPs are enriched for eQTLs and regulatory features specific to myeloid cells. Second, we aggregated AD GWAS SNP summary statistics at the gene and pathway level and found that genes critical for a key myeloid cell function, the phagocytic clearance of cellular debris (efferocytosis), are burdened by genetic variants associated with AD susceptibility. Using several endophenotypes to fine map GWAS loci we found that rs1057233, a SNP located in a previously reported AD risk locus near the CELF1 gene, showed association with higher age at onset (p=8.3×10-6), higher cerebrospinal fluid A?42 levels (p=1.2×10-4), and lower expression of SPI1/PU.1 in human macrophages (p = 6.41×10-87) and monocytes (p = 1.50×10-105). Rs1057233 has been shown to influence microRNA binding to the 3’-UTR of SPI1/PU.1, thereby modulating SPI1/PU.1 mRNA stability and gene expression. SPI1/PU.1, is a myeloid-specific transcription factor and a master regulator of myeloid cell development and function, including many of the genes associated with AD in the aforementioned pathway analysis. Based on these results, we propose that therapeutics that lower SPI1/PU.1 levels or modulate gene networks downstream of SPI1/PU.1 may be effective in reducing risk for AD.
11:35  Genetics of Gene Expression and its Effect on Neurodegenerative Disease
  Towfique Raj
Assistant Professor, Ronald M. Loeb Center for Alzheimer’s Disease
Icahn School of Medicine at Mount Sinai
  A steadily growing number of studies have identified and characterized expression and splicing quantitative trait loci (eQTLs) in human cell-lines, primary cells, and tissues. This class of genetic variation has been shown to play a role in complex traits, including disease. In this talk, I will discuss how eQTLs in primary immune cells have accelerated the discovery of disease genes and functional mechanisms underlying complex traits. I will discuss how context-specificity of eQTLs is being characterized at an unprecedented scale and breadth, and how this informs on the intricacy of human genome function. I will present results form the ImmVar project demonstrating remarkable polarization of functional effects on innate immune function for Alzheimer’s and Parkinson’s disease. This observation represents an important advance that significantly refines the emerging narrative of the role of the peripheral myeloid cells in susceptibility to neurodegenerative diseases. I will also present results from a comprehensive study of mRNA gene expression and splicing from the transcriptome of over 500 Alzheimer’s disease (AD) brains to demonstrate that AD susceptibility variants regulate the generation of aberrant mRNA splicing (sQTLs) through effects on RNA binding proteins, and that the splicing machinery is altered by the pathophysiology of AD. Together, these studies have important ramifications for elucidating function of genetic variants of interest, particularly for those contributing to neurodegenerative disease. These contributions provide a foundation for further mechanistic studies that will elucidate the drivers of disease, dissect the resulting causal chain leading to neurodegeneration and pave the way for future drug discovery efforts.
Discovering Epigenetic and Transcriptomic Mediators in Alzheimer’s disease
  Yongjin Park
Massachusetts Institute of Technology

Heritability of a complex disease trait is largely attributable to common genetic variants in noncoding regulatory regions, and it was demonstrated by systematic analyses on immune disease phenotypes that expression QTLs are enriched in GWA significant regions. However an effect size of each individual QTL is weakly penetrable to the disease phenotypes, and enrichment analysis of QTLs can be hampered by the lack of statistical power, incapable of identifying target regulatory elements and genes. Imputed transcriptome-wide association studies (iTWAS) by Gamazon et al. and Gusev et al. overcome difficulty of enrichment analysis and successfully demonstrated the strength of polygenic models–incorporating additive effects of multiple SNPs within cis-regions to test gene-level association with disease phenotypes.

In this talk I will present our approach to generalize the imputation framework in two ways: (1) We developed black-box variational Bayes algorithm that can relax linear Gaussian assumption of the link function in polygenic models, while controlling sparsity of the model by spike-slab prior on the regression coefficients. (2) We extended single-layered polygenic models, e.g., genetics to transcriptomics, to multi-layered models linking genetics to epigenetics, and then epigenetics to transcriptomics. In our analysis on the ROS/MAP Alzheimer’s disease (AD) cohort, we found DNA methylation variability is best modeled by non-conjugate Beta regression model with spike-slab prior. We compared different modeling strategies within a unified stochastic gradient variational Bayes (SGVB) framework in methylome-wide 5 fold cross-validation experiments. And we also confirmed accuracy of our stochastic gradient variational Bayes algorithm in realistic simulations. Our SGVB algorithms outperformed commonly used generalized linear models implemented with elastic-net prior. Using the beta regression models on each CpG probes we imputed association statistics between DNA methylation and AD phenotype, and we found significant CpGs supported by aggregate polygenic effects within non-GWA significant regions. Moreover our multi-layered QTL models identified novel AD associated genes that could only be explained by genetically controlled DNA methylation levels of cis-regulatory CpGs.

12:25 Lunch Provided by GTCbio & Conference Concludes