2017 Archived Content

CNS and Neurodegenerative Targets

The identification of therapeutic targets based on novel mechanistic approaches is urgently needed for CNS and neurodegenerative diseases, particularly for conditions such as Alzheimer’s which represent extensive unmet medical need and blockbuster potential for the right therapy.

Driven by an improving understanding of CNS disease biology and the emergence of new mechanisms and targets, Cambridge Healthtech Institute’s CNS and Neurodegenerative Targets symposium profiles the latest tools, targets and platforms driving today’s CNS drug discovery strategies, with critical updates and findings in key areas such as new targets for misfolded proteins, tau, GCPRs, kinase inhibitors, genetics, gene therapy, neuroinflammation, exosomes.

Final Agenda


• September 25 Symposium: Targeting Autophagy

• September 25 Short Course: Targeting of Ion Channels with Monoclonal Antibodies

• September 26-27 Conference: Lead Generation Strategies

• September 27-28 Conference: Kinase Inhibitor Discovery

• September 27 Short Course: Practical Phenotypic Screening

• September 28-29 Symposium: CNS and Neurodegenerative Targets

Thursday, September 28

4:00 pm Registration

CNS Discovery Strategies and Emerging Targets

5:25 Welcome Remarks

Daniel Barry, Senior Conference Director, Cambridge Healthtech Institute

5:30 Chairperson’s Opening Remarks

Gerry Higgins, Ph.D., M.D., Research Professor, Computational Medicine and Bioinformatics, University of Michigan Medical School

5:40 Developing a Novel Drug Discovery Platform for Identifying Potential Therapeutic Agents and Targets for the Treatment of Neurodegenerative Disease

Robert_ScannevinRobert H. Scannevin, Ph.D., Vice President, Discovery Biology, Yumanity Therapeutics

Typical approaches for identifying drug targets, such as human genetics, often fail to provide an appropriate cellular or pathological context, which is essential for the drug discovery process. Yumanity employs a yeast-based phenotypic discovery platform which is sensitive to neurodegenerative disease proteins. This platform allows for high throughput screening and target identification, and facilitates validation in other cell systems (e.g. iPSC).

6:10 Mining the Topography and Dynamics of the 4D Nucleome to Identify Novel CNS Drug Pathways

Gerry_HigginsGerry Higgins, Ph.D., M.D., Research Professor, Computational Medicine and Bioinformatics, University of Michigan Medical School

The regulatory non-coding genome contains the majority of genomic variants that are significantly associated with inter-individual variation in drug response. We developed a pharmacoepigenomic informatics pipeline that uses pharmacogenomic GWAS variants as inputs, which disrupt the functional topology of transcription as the primary defining characteristic of pharmacoepigenomic networks. Using this method, we have used network analysis which outputs significantly interconnected pharmacodynamic pathways for lithium and valproate in the human CNS.

6:40 Close of Day

Friday, September 29

8:00 am Registration and Morning Coffee

Targets for Alzheimer’s Disease - BACE, Tau

8:30 Chairperson’s Remarks

Matthew E. Kennedy, Ph.D., Director, Neuroscience, Merck Research Labs

8:40 The Promise and Challenge of BACE1 as a Therapeutic Target for Alzheimer’s Disease

Robert Vassar, Ph.D., Professor, Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University

The β-secretase, β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), is required to generate the β-amyloid peptide (Aβ) that plays an early critical role in Alzheimer’s disease (AD). Thus, BACE1 is a prime AD therapeutic target and several small molecule BACE1 inhibitor drugs are in AD clinical trials. However, the safety and efficacy of BACE1 inhibitors for AD are unknown. Moreover, BACE1 levels are elevated in AD brain, suggesting that the enzyme initiates a vicious cycle of Aβ production. My talk will discuss our results with BACE1 conditional knockout mice to model the safety of BACE1 inhibition in vivo. Additionally, I will discuss our efforts to understand the mechanism of BACE1 elevation in AD as a therapeutic target. Finally, I will summarize the current BACE1 inhibitor clinical trials and the prospects for BACE1 inhibition as a therapeutic approach for AD.

9:10 Targeting Ab and Tau Spreading for Disease Modification in Alzheimer’s Disease

Matthew_KennedyMatthew E. Kennedy, Ph.D., Director, Neuroscience, Merck Research Labs

I will discuss the discovery and clinical translation of the BACE inhibitor, verubecestat and review emerging strategies to target tau pathology in AD. How combination therapies targeting amyloid and tau pathology could improve chances of achieving efficacy across stages of AD will also be discussed.

9:40 Novel Therapeutic Targets against Tau Pathology: A Phenotypic Approach

Marija_UsenovicMarija Usenovic, Ph.D., Senior Scientist, Department of Neuroscience, Merck Research Laboratories, Merck & Co., Inc.

Increasing evidence suggests that tau pathology spreads throughout the brain via interconnected neurons. However, the molecular and cellular mechanisms of pathogenic tau transmission are not well established. We performed a phenotypic screen in hiPSC-neurons to identify molecular targets within cell-surface heparan sulfate proteoglycans that block tau oligomer uptake. Here we present the hits and novel therapeutic strategies that would inhibit tau pathology-spread and its consequences on neurodegeneration.

10:10 Networking Coffee Break

Targets for Alzheimer’s Disease - BACE, Tau (CONT.)

10:40 Development of Antibody against Early Disease Driver cis P-tau for Treating Alzheimer’s Disease and Brain Injury

Xiao_ZhouXiao Zhen Zhou, Ph.D., Assistant Professor, Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School

Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) share a common risk factor, traumatic brain injury (TBI) and neuropathological hallmark, neurofibrillary tangles. By developing tau conformation-specific antibodies, we have discovered that cis P-tau antibody can effectively eliminate cis P-tau, a precursor of tau pathology and early driver of neurodegeneration linking TBI to Alzheimer’s disease. Thus, cis P-tau antibody may be useful for treating Alzheimer’s disease and TBI at early stages.

11:10 Chemogenomic Screen Identifies Druggable Modulators of Axonal Transport of Mitochondria

Evgeny Shlevkov, PhD., Instructor in Neurobiology, Harvard Medical School

11:40 Sponsored Presentation (Opportunity Available)

12:10 pm Enjoy Lunch on Your Own

Neuroinflammation, Rare Diseases

1:45 Chairperson’s Remarks

S. Pablo Sardi, Ph.D., Pharm.D., R&D Director, Neuroscience, Sanofi

1:50 Targeting Lysosomal Defects in the Treatment of Parkinson’s Disease: From Genetics to Precision Medicine Trials

Pablo_SardiS. Pablo Sardi, Ph.D., Pharm.D., R&D Director, Neuroscience, Sanofi

Clinical, genetic and experimental evidence underlies the relevance of lysosomal dysfunction in Parkinson’s disease. Stimulation of the lysosomal GBA pathway in the CNS can ameliorate the pathological and behavioral abnormalities in animal models of disease. Modulation of this lysosomal pathway may represent a new disease-modifying treatment for Parkinson’s disease patients carrying GBA mutations. This research underscores the study of rare diseases as a new paradigm for drug discovery.

2:20 Modeling C9ORF72 Disease: A Crucial Step for Therapeutic Development in Amyotrophic Lateral Sclerosis and Dementia

Clotilde_Lagier-TourenneClotilde Lagier-Tourenne, M.D., Ph.D., Assistant Professor, Neurology, Massachusetts General Hospital and Harvard Medical School; Associate Member, Broad Institute

Repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Expression of expanded repeats caused age-dependent accumulation of RNA foci and dipeptide repeat proteins, accompanied by loss of hippocampal neurons and impaired cognitive function in transgenic mice. This model has been an essential tool to develop novel therapeutic approaches, including RNA-targeting antisense oligonucleotides and immunotherapies for patients with ALS/FTD.

2:50 Small Molecule Transforming Growth Factor (TGF-β) Enhancers Are Novel Therapeutic Agents to Prevent and Treat Progressive Neurodegenerative Diseases

Jung_HuangJung S. Huang, Ph.D., Professor, Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine

Pathogenic peptides/proteins, which are responsible for neurodegenerative diseases, are produced in plasma membrane lipid rafts in brain tissue. Promising agents for neurodegenerative diseases are predicted to possess activities to inhibit production of these peptides/proteins and enhance TGF-β activity which protects neurons and glial cells from injury/death. We discover novel TGF-β enhancers. They enhance TGF-β activity by disrupting lipid rafts. We predict that they are effective agents to prevent/treat neurodegenerative diseases.

3:20 Poster Presentation: Therapeutic Effects of a Novel HDAC6 Selective Inhibitor in In Vitro and In Vivo Models of Huntington’s Disease

Hyeri Sim, Senior Research Scientist, CKD Pharm

3:50 Close of Symposium