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Gene Targeting Therapies (Roy Alcalay) Recent Developments in Gene - Targeted Therapies for Parkinson’s Disease Roy Alcalay, MD, MS Alfred and Minnie Bressler Associate Professor of Neurology Division of Movement Disorders Columbia University Medical Center Disclosures Funding: Dr. Alcalay is funded by the National Institutes of Health, the DOD, the Michael J. Fox Foundation and the Parkinson’s Foundation. Dr. Alcalay receives consultation fees from Genzyme/Sanofi, Restorbio, Janssen, and Roche. Gene Localizations Identified in PD Gene Symbol Protein Transmission Chromosome PARK1 SNCA α-synuclein AD 4q22.1 PARK2 PRKN parkin (ubiquitin ligase) AR 6q26 PARK3 ? ? AD 2p13 PARK4 SNCA triplication α-synuclein AD 4q22.1 PARK5 UCH-L1 ubiquitin C-terminal AD 4p13 hydrolase-L1 PARK6 PINK1 PTEN-induced kinase 1 AR 1p36.12 PARK7 DJ-1 DJ-1 AR 1p36.23 PARK8 LRRK2 leucine rich repeat kinase 2 AD 12q12 PARK9 ATP13A2 lysosomal ATPase AR 1p36.13 PARK10 ? ? (Iceland) AR 1p32 PARK11 GIGYF2 GRB10-interacting GYF protein 2 AD 2q37.1 PARK12 ? ? X-R Xq21-q25 PARK13 HTRA2 serine protease AD 2p13.1 PARK14 PLA2G6 phospholipase A2 (INAD) AR 22q13.1 PARK15 FBXO7 F-box only protein 7 AR 22q12.3 PARK16 ? Discovered by GWAS ? 1q32 PARK17 VPS35 vacuolar protein sorting 35 AD 16q11.2 PARK18 EIF4G1 initiation of protein synth AD 3q27.1 PARK19 DNAJC6 auxilin AR 1p31.3 PARK20 SYNJ1 synaptojanin 1 AR 21q22.11 PARK21 DNAJC13 8/RME-8 AD 3q22.1 PARK22 CHCHD2 AD 7p11.2 PARK23 VPS13C AR 15q22 Gene Localizations Identified in PD Disorder Symbol Protein Transmission Chromosome PD GBA β-glucocerebrosidase AD 1q21 SCA2 ATXN2 ataxin-2 AD 12q23-24.1 SCA17 TBP TATA-binding protein AD 6q27 DYT5a GCH1 GTP cyclohydrolase 1 AD 4q22.1 DYT5b TH tyrosine hydroxylase AR 11p15.5 RIT2 locus via GWAS study GTPase ? 18q12.3 PDXK Pyridoxal kinase ? 21q22.3 HLA-DRA Human leukocyte antigen ? 6p21.3 SYNE1 Synaptic nuclear protein 1 ? 6q25 SLC6A3 Dopamine transporter AR 5p15.3 SLC30A10 Mn transporter AR 1q41 SPG11 spatacsin AR 15p21.1 FTD FUS Fusion gene AD 16p11.2 FTD/MND C9ORF72 ? AD 9p21 PD/ALS ANG angiogenin ? 14q11.2 PD DNAJC1 RME-8 AD 3q22.1 Juv PD SYNJ1 synaptojanin 1 AR 21q22.11 Juv PD DNAJC6 auxilin AR 1p31.3 Infant PD SLC18A2 VMAT2 AR 10q25 Frequency of Known Mutations at Columbia University (Source Studies: CORE-PD; Spot) • SNCA: exceedingly rare (2 confirmed cases) • PRKN: common when age-at-onset below 30 • LRRK2: 1% of the entire center; 15% of Ashkenazi Jews (AJ) with PD • GBA: 5% of the entire center; 20% of AJ with PD Genetics Risks for PD by Frequency and Risk A: Rare variants. Rare and highly penetrant B: Common variants. Low penetrance C: Intermediate variants. Intermediate penetrance and frequency Gene-Targeted Therapies for PD • Rare variants – future patient customized therapies, e.g., Kim el al 2019 • Common variants – common targets, e.g., immune therapies targeting a-synuclein • Intermediate variants – most advanced precision medicine for PD GBA LRRK2 Outline • LRRK2-related clinical trials – Epidemiology and Mechanism – Specific studies • GBA-related clinical trials – Epidemiology and Mechanism – Specific studies • Common questions and challenges Outline • LRRK2-related clinical trials – Epidemiology and Mechanism – Specific studies • GBA-related clinical trials – Epidemiology and Mechanism – Specific studies • Common questions and challenges LRRK2 Epidemiology • 1% of sporadic PD and 4% of familial PD carry LRRK2 mutations (Healy, 2008) • 40% of North African Berbers with PD (Lesage, 2006) • 14% of Ashkenazi Jews (AJ) with PD (Ozelius, 2006; Alcalay, 2013) • Gender distribution in LRRK2 is 50/50 (Orr-Urtreger, 2007) • Penetrance estimation by age 80 (Lee, 2017): – 25% AJ – 42.5% Non-AJ LRRK2 Kinase Activity • LRRK2 substrates: – Rab GTPases (Steger, 2016) – Autophosphorylation. (e.g., Serine 1292 residue) (Sheng, 2012) • Most, but not all, LRRK2 mutations are associated with increased kinase activity LRRK2 Kinase Activity • LRRK2 is abundantly expressed in the kidneys, lungs, pancreas, and certain cell types of the immune system (Schapansky, 2015) • LRRK2 inhibitors were developed promptly after the discovery of LRRK2, but clinical trials were postponed for concern for renal and/or pulmonary side-effects (lamellar bodies) Battista et al., 2018 LRRK2 in Urine Exosomes of G2019S Carriers with and without PD Frazer et al., Neurology. 2016 Urine BMP Levels by LRRK2 and PD Status Alcalay et al., 2019 LRRK2 in Idiopathic PD Di Maio, 2018 • Wildtype LRRK2 kinase activity is selectively enhanced in substantia nigra dopamine neurons in iPD. Outline • LRRK2-related clinical trials – Epidemiology and Mechanism – Specific studies • GBA-related clinical trials – Epidemiology and Mechanism – Specific studies DNL151 NCT04056689 • 2017: Phase I • 2020: Phase I-b – Enrollment: 34 people with PD with or without an LRRK2 mutations – Treatment: 3 doses for 28 days. – Primary outcome: comprises adverse events and laboratory tests, vital signs, ECG, or neurological exam. – Secondary outcomes: include pharmacokinetics, and LRRK2 and Rab10 phosphorylation in blood. – Status: The trial is delayed because of COVID-19. – Recruitment in Belgium, Netherlands, UK DNL201 NCT03710707 • 2018-2019: Phase Ib – Status: Completed – Enrollment: 29 PD patients with or without LRRK2 mutation – Treatment: Two doses • Primary outcomes: consisted of adverse events and abnormalities in laboratory tests, vital signs, ECG, or neurological exam. • Secondary outcomes: included pharmacokinetics, and LRRK2 and Rab10 phosphorylation. Also, BMP in urine. • In a January 2020 Denali announced that both doses achieved more than 50 percent inhibition of LRRK2 and Rab10 phosphorylation in blood, and improved BMP in urine BIIB094 NCT03976349 • Antisense oligonucleotide (ASO) • Binds the mRNA for LRRK2 and mediates its degradation. • 2019: Phase I safety trial – Enrollment: 62 participants, with or without a LRRK2 mutation – Treatment: Intrathecal injection, a single dose, multiple doses, or placebo. – Primary outcome: adverse events or serious adverse events for up to one year after injection. – Secondary outcomes: include pharmacokinetics of the ASO in blood. – Sites: 15 centers in Israel, North America, Norway, Spain and the U.K. Additional Studies • GSK NCT01424475 • Genentech • Merck • Pfizer Outline • LRRK2-related clinical trials – Epidemiology and Mechanism – Specific studies • GBA-related clinical trials – Epidemiology and Mechanism – Specific studies • Common questions and challenges Gaucher Disease • Common lysosomal storage disorder • Autosomal recessive: caused by mutations in glucocerebrosidase (GBA) • Leads to deficiency of the lysosomal enzyme Glucocerebrosidase (GCase) • Divided into three types: – Type 1 (non-neuronopathic) – Types 2 and 3 (neuronopathic) GBA/PD Epidemiology • 3% of PD patients carry either the N370S or the L444P GBA mutations (Sidransky, 2009) • 5-10% of PD patients carry a GBA mutation or variant (Gan-Or, 2015) • 35% of all Ashkenazi Jews (AJ) with PD are carriers of either GBA or LRRK2 mutations (Aharon-Peretz, 2004; Gan-Or, 2008; Clark 2008; Alcalay, 2010) • Penetrance estimation between 10-30% Gaucher Disease: Pathology Gaucher cells filled with glycosphingolipids accumulate in the reticuloendothelial system Glucocerebrosidase Pathway GBA/PD Mechanism: Loss or Gain? Gain of Function Loss of Function Biomarkers: GCase Activity • GCase activity is reduced in GBA carriers and Gaucher patients • GCase activity is reduced in autopsies of iPD cases, without GBA mutations (Gegg, 2012; Murphy, 2014; Clark, 2015) • Mildly reduced GCase activity peripherally in iPD compared to controls (Alcalay, 2015) • Among iPD, low GCase activity may be associated with faster disease progression (Alcalay, 2015) Outline • LRRK2-related clinical trials – Epidemiology and Mechanism – Specific studies • GBA-related clinical trials – Epidemiology and Mechanism – Specific studies • Common questions and challenges Ambroxol (Aim PD) NCT02941822 • Licensed in the EU as an over-the-counter drug (mucolytic). • Aim PD: – Design: Phase IIA prospective, single-center, open label – Treatment: Escalating dose up to 1.26g a day (x10 fold) – Primary outcome: GCase and ambroxol levels in blood and CSF – Secondary outcome: treatment related adverse events, pharmacodynamics and biomarkers – Other outcomes: performance on motor and cognitive scales Ambroxol (Aim PD) NCT02941822 - cont. • Enrollment: Recruited 17 PD patients (8 GBA-PD, 9 non- GBA PD) • Results: – Ambroxol levels in CSF was equal to 11% of blood serum levels. – CSF GCase protein increased (35%; P = .002) – CSF GCase activity reduced by 19% (P = 0.04) – CSF α-synuclein increased (13%; P = 0.01) Venglustat (GZ/SAR402671) NCT02906020 • Brain-penetrant inhibitor of glucosylceramide synthase • Clinical trials in Gaucher, Fabry, autosomal dominant polycystic kidneys, Tay-Sachs and PD • Phase I: drug levels in plasma and CSF increased in a dose-dependent fashion; plasma and CSF glucosylceramide levels declined by up to 75 percent (Peterscmitt et al., 2019). • In 2016, MOVES-PD launched Venglustat (GZ/SAR402671) NCT02906020 – cont. • Enrollment: 270 participants with GBA variants • Treatment: One year regimen of once-daily drug or placebo, plus two years of follow-up. • Primary outcome: Change from baseline to one year on the UPDRS Part II and III • Secondary outcomes: Change in other PD cognitive and motor outcomes • Status: The treatment phase planned to finish in Dec. 2020. Trial completion in 2023. LTI-291 NL7061 (NTR7299) • LTI-291 is a small-molecule activator of Gcase • Completed Phase Ib study
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