Translating Scientific Discovery into Better Care: Groundbreaking - PowerPoint PPT Presentation

Translating Scientific Discovery into Better Care: Groundbreaking Research at the National Institute on Aging Friends of the NIA Briefing Richard J. Hodes, M.D., Director Marie A. Bernard, M.D., Deputy Director National Institute on Aging May 9, 2018

APPROPRIATIONS & FUNDING

$500M for Opioids $37 Billion $140M for BRAIN $60M for All of US for the NIH $414M for AD • $2.6B for the NIA • $111M increase for non-targeted NIA research; percent increase comparable to other ICs • All divisions will benefit  DBSR  DAB  DGCG  DN

Appropriations 2011 2012 2013 2014 2015 2016 2017 2018 National $50 M* $40 M* $100 M $25 M $350 M $400 M Alzheimer’s redirected redirected additional additional additional additional Project Act within NIH within NIH approp approp approp approp (NAPA) budget budget $414 M in additional appropriations as of 3/23/18 *one-year money Years displayed are Fiscal Years

NIA Appropriations Fiscal Years 2013-2018 $3,000 $2,574 $2,500 Dollars (in millions) $2,049 $2,000 $1,596 $1,500 $1,198 $1,172 $1,046 $1,000 $500 $0 2013 2014 2015 2016 2017 2018 NIA Funds AD funds

Total Active AD/ADRD FOAs 20 13 11 10 6 4 3 Basic Translation Clinical Trials Caregiving & Resource Health Training Research Clinical Care Leverage Disparities 6

New Investigator (NI) and Early Stage Investigator (ESI) AD/ADRD Awardees FY2015-2017 Number of AD/ADRD 500 452 450 400 Awardees 350 300 250 200 120 150 67 100 27% 50 15% 0 R01 and RF1 ESI Total NI/ ESI Awardees ESI : Early Stage Investigator NI : New Investigator

ADVANCING AGING RESEARCH

Intramural Research Program • 10 Intramural Laboratories • Core facilities • Home of the BLSA and HANDLS

NIA Laboratory of Neurogenetics • Found >90% of the genes and risk factors for Parkinson’s disease • Identified the first rare risk variant for Alzheimer’s disease ( TREM2 ) • Identified multiple genes for Amyotrophic Lateral Sclerosis and frontotemporal dementia, including the most common cause (c9orf72)

Identified: Created foundational data • >90% of genes and risk factors to link these gene for PD products together, to • The first rare risk variant for AD provide insights regarding • The most common disease- biology, mechanisms, and causing mutations in ALS and potential druggable FTD targets Understand the Target Identify the locus Find the gene pathobiology Identification dissect the disease Identified: Treatment • A classifier of PD case status that works with 98.7% Both SNCA level, accuracy at first and LRRK2 kinase presentation activity are in • A classifier that detects development as apparent PD cases that targets for PD aren’t really PD

Amyloid Deposition is Associated with Motor Impairment Before Cognitive Decline Gait maintainers Gait decliners Tian, Q et al. (2017). J Gerontol A Biol Sci Med Sci 72(5):716-723.

Division of Aging Biology • Nathan Shock Centers of Excellence • Genetics and Cell Biology • Genetics • Cell Biology • Metabolic Regulation • Aging Physiology Caenorhabditis Rotifers Mus Monkeys elegans • Stem cells & Regenerative Biology musculus Saccharomyces • Immunology cerevisiae Homo • Endocrinology Sapiens Rats Hydra Drosophila melanogaster Dogs • Musculoskeletal Biology • Tissue Physiology Director: Felipe Sierra, Ph.D. sierraf@nia.nih.gov • Biological Resources Deputy Director: Ron Kohanski, Ph.D. • Animal Models kohanskir@nia.nih.gov • Biological Resources

“ Geroscience ” is the Convergence of Two Fields of Study Vascular Neurological Disease Disease Arthritis Macular Macromolecular Biology Degeneration Hearing CKD Sarcopenia Damage of Stress Disease Cancer Epigenetics Response Immunity COPD Heart Disease Other Stem Biology Cells Stem Proteostasis Cells Biology Epigenetics Metabolism Proteostasis of Inflammation Metabolism Inflammation Aging Immunity Damage (Repair) Stress Genetics (Adaptation) Burch, JB et al. (2014) J Gerontol A Biol Sci Med Sc i Jun; 69 Suppl 1:S1-3;Kennedy, BK et al. (2014) Cell 159(4): 709 – 713.

Chemotherapy-induced fatigue is diminished by removing senescent cells In humans, chemotherapy-induced fatigue correlates positively with senescent cell burden In mice, elimination of senescent cells diminishes side effects of chemotherapy Toxicity Chemotherapy Chemotherapy + Senolytic Inflammation +++ + Fatigue +++ - Cardiac - ++ dysfunction Myelosuppression ++ - - + + Doxo Cancer relapse +++ + - - + Gancyclovir Demaria, M. et al. (2017). Cancer Discovery 7(2):165-176

TIMP2 from Human Umbilical Cord Plasma Revitalizes Hippocampal Function in Aged Mice Synaptic Plasticity Cognitive Effect Castellano, J.M. et al. (2017). Nature 544(7651):488-492

Division of Neuroscience • Basic Neurobiology • Alzheimer’s Disease • Sensory Processes • Learning and Memory • Sleep • Cognitive Health Director: Eliezer Masliah, M.D. Eliezer.Masliah@nih.gov Acting Deputy Director: Brad Wise, Ph.D. wiseb@nia.nih.gov

What Counts as AD/ADRD Research? • The AD/ADRD payline applies to applications/awards that are coded as AD or Alzheimer’s disease - related dementias (ADRD) • The ADRD RCDC categories that report related dementias specifically named in the National Plan to Address Alzheimer’s Disease are:  Lewy Body dementia (LBD)  Frontotemporal dementia (FTD)  Vascular Cognitive Impairment/Dementia (VCI/D)

Diversity of AD/ADRD Research Aging Comparative Basic Biological metabolic biology of Processes of AD neurodegeneration changes in AD Geroscience Biomarkers Research on Research on Care and Disease Caregiver Alzheimer’s Mechanisms Support Research Cognitive Disparities, Sex outcomes in differences, Population and AD risk Studies

What is CRISPR & How are we using it? Studying human genes in human brain cells Somatic Cells It’s part of a bacterial defense system that Reprogramming allows us to “edit” a genome IPSCs CRISPR/Cas: e.g., APOE3/4, GWAS variants (studies in progress) Neurons Microglia Organoid Astrocytes Oligodendrocytes Modified from Mungenast et al., Mol Cell Neurosci , 2016, 73 :13-31.

Studying human genes in human brain cells Somatic Cells Accelerating Aging: RFA-AG17-009 e.g., Progerin, ERCC; CRISPR/Cas TERT, Klotho Neurons Microglia Reprogramming Organoid Astrocytes Oligodendrocytes IPSCs CRISPR/Cas: e.g., APOE3/4, GWAS variants (studies in progress) Neurons Microglia Organoid Astrocytes Oligodendrocytes Modified from Mungenast et al., Mol Cell Neurosci , 2016, 73 :13-31.

Studying human genes in human brain cells Somatic Cells Accelerating Aging: RFA-AG17-009 e.g., Progerin, ERCC; CRISPR/Cas TERT, Klotho Neurons Microglia Reprogramming Organoid Functional Astrocytes Oligodendrocytes Genetics of AD: RFA-AG14-012, IPSCs RFA-AG17-053 CRISPR/Cas: e.g., APOE3/4, AD Phenotypes GWAS variants (studies in progress) A β Endosome Trafficking Neurons Microglia Tau Organoid RNA, Synaptic Dysfunction Astrocytes Oligodendrocytes epigenetics, chromatin Immunomodulation Modified from Mungenast et al., Mol Cell Neurosci , 2016, 73 :13-31.

Aducanumab Reduces Amyloid β plaques in AD One Year Baseline Placebo 3 mg kg -1 6 mg kg -1 10 mg kg -1 Sevigny J. et al. (2016). Nature . 537(7618):50-6.

Accelerating Medicines Partnership Alzheimer’s Disease Program Managing Partner https://www.nia.nih.gov/alzheimers/amp-ad

Accelerating Medicines Partnership – AD Knowledge Portal Predictive Target Discovery Biomarkers in and Preclinical Secondary Validation Prevention Trials AMP-AD Knowledge Portal (SAGE)

Accelerating Medicines Partnership – AD Knowledge Portal A hub for data, analysis results, analytical methodology and research tools Researchers can use it for: Data Integration (learning from large pools of data) Predictive Modeling (using what we know to better match compounds to targets) Molecular Profiling (understanding new targets better) Experimental Validation (testing interventions in models) + Rapid and Broad Sharing (of what we are learning) https://www.synapse.org/#!Synapse:syn2580853/wiki/409840

AMP-AD Mount Sinai Team Candidate Targets: Preliminary list Rank Driver Rank Driver 1 RGS4 26 SV2B 2 SCN2A 27 RBFOX1 3 OLFM3 28 STAT4 “Wall” of 4 SLC22A10 29 PAK1 5 ENAH 30 RASAL2 6 WWTR1 31 SYT1 Targets - Over 7 LRP10 32 NCKAP1L 8 SYP 33 PARD3B 9 PCSK1 34 TLN1 100 novel 10 KMO 35 NRXN1 11 PTTG1IP 36 TNFRSF1B 12 MLIP 37 ARHGEF9 targets 13 PLXNB1 38 DUSP4 14 DLGAP1 39 DTX3L 15 MOAP1 40 SNAP25 discovered 16 PRKCB 41 PLCB1 17 VGF 42 WDR49 43 NFIA 18 YAP1 44 XK 19 GNA13 45 NAPB 20 TRIM56 46 MVP 21 KCNV1 47 GABRA1 22 STXBP5L 48 CD68 23 DOCK2 49 LAPTM5 24 GABRG2 50 ANGPT1 25 STAT3