UCSF Movement Disorders Neurology Research /Support Staff Jill - PowerPoint PPT Presentation

2/15/2018 UCSF Movement Disorders Neurology Research /Support Staff Jill Ostrem, MD Sarah Wang, PhD Nicholas Galifianakis, MD Kristen Dodenhoff, BA Caroline Tanner, MD, PhD Farah Kauser Marta San Luciano, MD Joncarmen Mergenthaler Maya Katz, MD Janet Allen Ian Bledsoe, MD,MS Shatara Blackmon James Maas, MD, PHD Yasmeen Gonzalez New Directions in Movement Disorders Chadwick Christine, MD Jeverly Calaunan Michael Aminoff, MD Kathleen Comyns, MPH Robert Edwards, MD Samantha Betheil, BA Caroline Tanner, MD, PHD Ken Nakamura, MD, PhD Cheryl Meng, MPH Alexandra Nelson, MD, PhD Jill Ostrem, MD Danilo Romero Michael Geschwind, MD Kanchi Mehta Amy Viehoever, MD, PhD Nijee Luthra, MD, PhD Psychiatry UCSF Movement Disorder and Neuromodulation Center Cameron Dietiker, MD Andrea Seritan, MD Recent Advances in Neurology 2018 Neurosurgery Social Work Neuropsychology Philip Starr, MD, PhD Monica Eisenhardt, LCSW Caroline Racine Belkoura, PhD Fellows Paul S. Larson, MD Jessica Weinstein, MD Edward F. Chang, MD Chaplin Nursing Kyle Mitchell, MD Daniel Lim, MD, PhD Judith Long Monica Volz, FNP, MS Jennifer Choi, MD Krzysztof Bankiewicz, MD, PhD Karen Merchant, MSN Ethan Brown, MD Coralie De Hemptinne, PhD Physical Therapy Susan Heath, MS, RN Mitra Afshari, MD UCSF Weill Whitney Chen, PhD Nancy Byl, PT, PhD Gina Bringas-Cinco, RN Melissa Heiry, MD Heather Bhide, PT Doris Wang, MD, PhD Annie Li Wong, NP Idit Tamir, MD, PhD Institute of Neurosciences Disclosures New Direction #1 • Parkinson’s Disease is not one disease Caroline Tanner, MD, PHD • An employee of the San Francisco Veterans Affairs Medical Center and the University and will be better managed with an of California – San Francisco. • Receives grants: the Michael J. Fox Foundation, the Parkinson’s Disease Foundation, individual treatment approach the Department of Defense, BioElectron, Roche/Genentech and the National Institutes of Health, • Compensation for serving on Data Monitoring Committees: Biotie Therapeutics, Voyager Therapeutics and Intec Pharma • Personal fees for consulting: Neurocrine Biosciences, Adamas Therapeutics, PhotoPharmics , 23andMe and Alexza Jill Ostrem, MD • Consultant and speaker: Allergan Inc., Medtronic Inc. • Educational grant support: Medtronic Inc, Allergan Inc, AbbVie Inc, Boston Scientific Inc. • Clinical trial support: Ceregene Inc., St. Jude Medical, Inc, Boston Scientific Inc, Cala Health Inc, Google Inc

2/15/2018 One Disease or Many? PD Subtypes 5 jamanetwork.com PD Genetics PD Genetics– Targeted Therapies Gene Mutations Protein/Enzyme Function Age at Phenotype Pathology Genetic influence increasingly recognized onset Dominantly inherited last-onset PD Monogenic forms (Mendelian inheritance)= mutation in single gene sufficient to SNCA Missense Alpha synuclein- structural 60 yr Levodopa responsive Diffuse lewy bodies cause PD brain protein (30-80) SNCA Locus duplication (and 31-71 yr Levodopa responsive, younger age, rapid Diffuse lewy bodies, 30% of all familial cases triplication) progression, autonomic dysfunction, dementia, prominent nigral and wide spread Lewy Bodies hippocampal loss ~5% of sporadic cases LRRK2 Missense: Arg Leucine-rich repeat kinase 60 yrs Levodopa responsive, Like sporadic PD, slow Brain Stem LB, 1441Cys/Gyl/His; 2- enzyme when mutated (32-79) progression, abduction-addition lower limb neurofibrillary tangle or Six regions contain genes that conclusively cause PD Try1688Cys, Gly2019Ser, causes Lewy-body tremor, little dementia TDP-43 pathology and/or IIe2020Thr phenotype –increased nigral neuronal loss kinase activity Polymorphisms, protective haplotypes The cause of PD is multifactorial VPS35 Missense: ASP620Asn 53 yrs Levodopa responsive tremor-dominant, Inconclusive- ? No LB (40-68) dyskinesia and dystonia, occasionally dementia • Several genes Juvenile and early-onset recessively inherited PD • Modifying effects of susceptibility factors PARK2 Numerous missence, exon Parkin- a ubiquitin-protein <45yr Levodopa responsive, early dystonia, slow Predominantly nigral deletion and duplication ligase involved in protein (12-58) progression, hyperreflexia, dyskinesia, early neuronal loss 15-50% • Environmental exposures mutations degradation gait and balance issues, less non-motor Occasionally with synuclein or tau pathology • Gene-environment interactions ~5% Parkin PINK1 Misssence: many PTEN-induces putative <45yr (18- Levodopa responsive, akinetic/ridgid postural One case with lewy bodies Penetrance/ DJ-1 kinase 56) instability, gait, slow progression, sleep benefit LRRK2 Rare: locus and exon Effect Size PINK1 deletion SNCA SNCA VPS35 DJ-1 Misense: Glu163lys, Leu Positive regulator of <40 yr Like PINK-1, rare Unknown 166Pro Exon 1-5 deletion, androgen- receptor (24-39) Young-onset Age at onset of PD Late-onset g.168-185 dup dependent transcription 7

2/15/2018 PD Mechanisms of Disease LRRK2 Mutation • Mutation in the leucine rich repeat kinase 2 (LRRK2) gene (G2019S) is Protein trafficking the greatest known genetic cause of PD • ubiquitin/protease system • Most common monogenic cause of PD in Europe and North America • alpha-synuclein • 30% penetrance Calcium-channel • Mutations seem to heighten the activity of LRRK2 kinase • apoptosis Inflammation Oxidative stress Phenotype • Like sporadic PD (later onset) Mitochondrial dysfunction • Variable clinical and pathological phenotype • Levodopa responsive • Slow progression • Abduction-addition lower limb tremor • Little dementia Video Courtesy of Dr. San Luciano and Darel Ogbonna Trinh J and Farrer M Nature Review, 2013. PD and GBA Mutation LRRK2 Treatment Approaches GBA mutations cause dysfunction in the LRRK2 based treatment glucocerebrosidase (Gcase) protein- leading • Inhibitors of LRRK2 kinase activity could potentially be used to to build-up of alpha-synuclein prevent or treat PD More common in Ashkenazi Jewish descent /Gaucher or relative with Gaucher (lipids Denali Therapeutics build up and enlarge organs) • Completed phase I study in control volunteers in 12/2017. • Reported 90% inhibition of LRRK2 activity (target engagement) Video Courtesy of Dr. San Luciano and Darel Ogbonna Phenotype • Well tolerated • Slightly earlier age of onset • Also testing a second compound in Phase I study. • Initial symptom often • Likely these drugs will move into phase II trial in LRRK2 PD bradykinesia • More rapid motor disease patients next. 5-10 % of PD patients carry this mutation progression, more dyskinesia GBA mutation - 20X increased risk of PD • More cognitive dysfunction GBA mutations are common but overall • Less tremor chance of PD is still low • More depression

2/15/2018 GBA Treatment Approaches Mitochondrial Dysfunction in Genetic PD • Overwhelming evidence implicates Sanofi / Genzyme mitochondrial function being compromised • Small molecule (GZ/SAR402671) in Parkinson’s disease Venglustat -targeting cellular • Oxidative stress is found in PD tissue dysfunction in PD patients with a GBA mutation (also for Gaucher Type III Especially for genetic subtypes: disease and Fabry disease) • Parkin • PINK1 • Glucosylceramide synthesis inhibitor Video Courtesy of Dr. Ian Bledsoe • DJ-1 Heterozygous carrier of N370S mutation • LRKK2 • Pre-clinical GBS mutation PD models treated with similar compound had fewer alpha-synuclein aggregation and did better on memory tests • Energy failure leads to neuronal cell death • Nigral dopaminergic neurons seem to be • Phase II international trial enrolling PD patients with GBA mutations (N=230) selectively vulnerable to energy failure • First industry – sponsored Phase II clinical trial in genetically defined PD • Energy-based therapies have generally failed population in their application in PD Mitochondrial Based Therapies Bioelectron – EPI-589 A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype and Idiopathic Parkinson’s Disease Subjects Phenotype: Parkin- a ubiquitin-protein ligase • (R)-troloxamide quinone (EPI-589) is a vitamin E derivative and ORALLY available drug involved in protein degradation Numerous missense, exon deletion • Aids in the catalysis of glutathione, an important and duplication mutations, No LB? antioxidant that aids in reducing oxidative stress • Glutathione depletion has been linked to Phenotype: mitochondrial dysfunction Levodopa responsive, dystonia, Video Courtesy of Dr. Nick Galifianakis akinetic/ridged, postural instability, Parkin Mutation PD • Being developed for treatment of neurological gait, slow progression, sleep benefit diseases characterized by high levels of oxidative Caldwell, 2008 stress and mitochondrial pathology (i.e. ALS, PD, HD, mitochondrial diseases) DJ-1: Mitochondrial regulation, antioxidative stress, chaperone PARKIN: Mitochondrial autophagy, ubiquitin-protease system • Focus on safety and quantifying glutathione cycle PINK1: Mitochondrial serine/threonine-protein kinase, protects against mitochondrial dysregulation biomarkers LRRK2: modulates mitochondrial dynamics and function