SLA e FTD: meccanismi di malattia ed opzioni terapeutiche

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1 SLA e FTD: meccanismi di malattia ed opzioni terapeutiche Vincenzo Silani U.O. Neurologia-Stroke Unit Centro Dino Ferrari IRCCS Istituto Auxologico Italiano Università degli Studi di Milano 1

2 ALS: disease due to MN selective vulnerability El Escorial (1990) Nature, 1993 Airlie House (1994) Airlie House (1998) WFN (1999) clinical trial guidelines Awaji Consensus (2008) Revised El Escorial (2015) Airlie House (2016) ALS: extramotor features Marie, 1892 Dornbluth, 1889 Raymond, Cestan, 1905 Fragnito, 1907 van Bogaert 1925 Meyer, 1929 Zieger, 1930 Braunmuhl, 1932 (single case report, link ALS-Pick) De Caro, 1941 Michaux, 1951 Delay, 1959 Van Reeth, Coers e van Bogaert, 1961 but Poloni et al. 1986: no ci/bi deficits in ALS! 2

3 Annali di Neurologia, 25, ,

4 Ludo van Bogaert ( ) 4

5 ALS Leigh e Lowe ( ): Ubiquitin Ubiquitin 2006 TDP

6 ALS-FTSD: clinical continuum (2017) Charcot plus ALS ALScbi Strong et al.,

7 Italian parallel versions B and C (Poletti et al, 2017) ALS and FTD: extremes phenotype spectrum of a single disease van Es et al.,

8 Ann Neurol, May 2013 Heiko Braak bvftd ALS Burrel et al., 2016 Genetics of ALS: UMN-LMN-extramotor continuum FTD GRN MAPT TREM2 hnrnps c9orf72 UBQLN2 CHMP2B OPTN VCP ALS-FTD SQSTM1 SPG11 LMN ERBB4 MATR3 VAPB SOD1 SETX FIG4 PFN1 UMN ALS2 TUBA4A FUS ATXN2 ANG TARDBP ALS 8

9 C9orf72: the neuronal selective vulnerability Psychiatric Diseases Knock et al ALS/FTD Genetics in Italy The SLAGEN CONSORTIUM ( > 4000 cases) Gene Frequency FALS SALS C9orf % 5.1% SOD1 11.0% 1.3% FUS 6.7% 1.2% TARDBP 4.1% 2.5% ANG 3.0% 0.5% UBQLN2 1.8% 0.1% OPTN 1.2% 0.5% PFN1 1.0% 0.1% Altri geni <1.0% 0% Totale 52.7% 11.3% (TARDBP) (SOD1) (C9orf72) 9

10 October, ALS/FTD : genes and major categories of pathophysiological processes Brown and Al-Chalabi,

11 Continuum SLA /FTD TBK1 Hardy and Rogaeva,

12 The special case of C9orf72-ALS/FTD Haeusler et al., Nat Rev Neurosci 2016 Rohrer et al., Lancet Neurol 2015 Rohrer et al., Lancet Neurol 2015 C9orf72: possible pathomechanisms LOSS OF FUNCTION GAIN OF FUNCTION Ling et al, Neuron

13 RAN translation (Repeat-associated Non-ATG translation) (GR)n (GP)n (GA)n Aggregated of dipeptide repeats in different areas of C9orf72+ patients Dipeptides Repeats (DR) RAN-dipeptides in CSF: a C9-specific biomarker Poly(GP) (Gendron et al., Acta Neuropathol 2013) Meso Scale Discovery 13

14 CSF poly(gp) in C9-ALS and C9-FTD (Lehmer et al., EMBO Mol Med 2017) No association with clinical variables (Lehmer et al., EMBO Mol Med 2017) 14

15 Poly(GP) as a pharmacodynamic biomarker mouse Gendron et al., Sci Transl Med

16 Ann Neurol 2017 Longitudinal study 16

17 Molecularly tailored interventions in ALS: genes * Zou et al.,

18 Autoptic Case: elimination half-life 30 days 2013 ASO-mediated C9orf72 reductions should be tolerated in the adult CNS ASOs C9orf72 April

19 DPR reduction with antisense oligonucleotides (ASO) C9orf72 lymphoblasts C9orf72 ipsc-neurons Gendron et al., 2017 C9ORF72: C9orf72 approcci - ASO terapeutici Therapy Antisense oligonucleotide (ASO) Lagierre-Tourenne et al, PNAS

20 C9ORF72: approcci terapeutici C9orf72 - Small Molecule Therapy Small molecules binding G 4 C 2 RNA < foci < DPR ALS/FTD: Precision Medicine 20

21 Continuum Bertram and Tanzi, J Clin Inv 2005 FTD and ALS FDA approved: - none FDA approved: - Riluzole (1995) - Edaravone (2017) Ittner et al.,

22 ALS-FTD as a historical continuum FTLD 10% 10% social bvftd cognitive FTD impairment FTDbvFTD MND ALS- ALSbi/ci 40-45% language non-fluent fluent PNFA SD lvppa ALS-PNFA ALS-SD no cognitive impairment 55-60% PMA ALS PLS IRCCS Istituto Auxologico Italiano Centro Dino Ferrari Università degli Studi di Milano ICGEB Trieste Francisco E. Baralle Emanuele Buratti Fondazione IRCCS Istituto Carlo Besta Cinzia Gellera Franco Taroni, Giuseppe Lauria Dept. Neurology- Stroke Unit Laura Adobbati Luca Campana Andrea Ciammola Barbara Corrà Alberto Doretti Riccardo Doronzo Alessandra Gnesa Annalisa Lafronza Carolina Lombardi Luca Maderna Stefano Messina Claudia Morelli Barbara Poletti Davide Sangalli Ignazio Keller Sarmiento Federica Solca Nicola Ticozzi Federico Verde Laboratory of Neuroscience Isabella Fogh Niccolò Mencacci Antonia Ratti Patrizia Bossolasco Claudia Colombrita Lidia Cova Valentina Gumina Annamaria Maraschi Francesca Sassone Cinzia Tiloca Clara Volpe London, UK Chicago, USA UMass Medical School John E. Landers Chi-Hong Wu, Jenni Adams, Desiree M. Baron, Daryl A. Bosco, Robert H. Brown Jr. Claudia Fallini Mayo Clinic Jacksonville, FL Tania Gendron Leonard Petruccelli 22

23 ITALIAN SLAGEN CONSORTIUM IRCCS Istituto Auxologico Italiano UniMI Vincenzo Silani, Isabella Fogh, Nicola Ticozzi, Antonia Ratti IRCCS Istituto C. Besta - Milano Cinzia Gellera, Franco Taroni, Giuseppe Lauria Fabio Blandini Ospedale Maggiore - UniMI Giacomo Comi, Stefania Corti, Roberto Del Bo IRCCS Istituto Neurologico Casimiro Mondino Cristina Cereda, Mauro Ceroni Università del Piemonte Orientale Sandra D Alfonso, Lucia Corrado, Letizia Mazzini Cristina Cereda Università di Padova Gianni Sorarù Università degli Studi di Brescia Ospedali Civilli Massimiliano Filosto, Alessandro Padovani Università degli Studi di Pisa Gabriele Siciliano Università La Sapienza, Roma Mauro Ceroni Maurizio Inghilleri Un ulteriore ringraziamento a Pavia! Cesare S. Silani 23