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11/12/2017
1
SLA e FTD: meccanismi di malattia ed opzioni terapeutiche
Vincenzo Silani
U.O. Neurologia-Stroke UnitCentro “Dino Ferrari”
IRCCS Istituto Auxologico ItalianoUniversità degli Studi di Milano
11/12/2017
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El Escorial (1990)
Airlie House (1994)
Airlie House (1998)
WFN (1999)clinical trial guidelines
Awaji Consensus (2008)
Revised El Escorial (2015)
Airlie House (2016)
Nature, 1993
ALS: disease due to MN selective vulnerability
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!
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Annali di Neurologia, 25, 273-287, 1907
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Ludo van Bogaert(1897-1989)
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Leigh e Lowe (1988- 2006): Ubiquitin
ALS
2006
TDP-43
Ubiquitin
2008
2006……..
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ALS-FTSD: clinical continuum (2017)
Strong et al., 2017
ALScbi
“Charcot plus ALS”
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Italian parallel versions B and C (Poletti et al, 2017)
ALS and FTD: extremes phenotype spectrumof a single disease
van Es et al., 2017
11/12/2017
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Burrel et al., 2016
bvFTD ALS
Ann Neurol, May 2013
Heiko Braak
UMN
FTD
LMN
MAPTGRN
c9orf72
SOD1
UBQLN2
SQSTM1
VCP
CHMP2B
TREM2
hnRNPs
VAPB
OPTN
FUS
ANGATXN2
PFN1
TUBA4A
SPG11
SETX
ALS2
FIG4
ERBB4
MATR3
TARDBP
Genetics of ALS: UMN-LMN-extramotor continuum
ALS
ALS-FTD
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Knock et al. 2014
Psychiatric Diseases
C9orf72: the neuronal selective vulnerability…
(SOD1)
(TARDBP)
(C9orf72)
Gene Frequency
FALS SALS
C9orf72 23.9% 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%
ALS/FTD Genetics in ItalyThe SLAGEN CONSORTIUM ( > 4000 cases)
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October, 2013
177 190
107 103
ALS/FTD : genes and major categories ofpathophysiological processes
Brown and Al-Chalabi, 2017
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Hardy and Rogaeva, 2014
Continuum SLA /FTD
TBK1
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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
Ling et al, Neuron 2013
LOSS OF FUNCTION
GAIN OF FUNCTION
C9orf72: possible pathomechanisms
11/12/2017
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RAN translation(Repeat-associated Non-ATG translation)
(GA)n
(GR)n(GP)n
Dipeptides Repeats (DR)
Aggregated of dipeptide repeats in different areas of C9orf72+ patients
RAN-dipeptides in CSF: a C9-specific biomarker
(Gendron et al., Acta Neuropathol 2013)
Poly(GP)
Meso Scale Discovery
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(Lehmer et al., EMBO Mol Med 2017)
CSF poly(GP) in C9-ALS and C9-FTD
(Lehmer et al., EMBO Mol Med 2017)
No association with clinical variables
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Gendron et al., Sci Transl Med 2017
Poly(GP) as a pharmacodynamic biomarker
mouse
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Ann Neurol 2017 Longitudinal study
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Zou et al., 2016
Molecularly tailored interventions in ALS: genes
*
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Autoptic Case: elimination half-life 30 days
2013
“ASO-mediated C9orf72 reductions should be tolerated in the adult CNS”
April 2016ASOs C9orf72
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Gendron et al., 2017
DPR reduction with antisense oligonucleotides (ASO)
C9orf72 lymphoblasts C9orf72 iPSC-neurons
Antisense oligonucleotide (ASO)
C9ORF72: approcci terapeutici
Lagierre-Tourenne et al, PNAS 2014
C9orf72 - ASO Therapy
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C9ORF72: approcci terapeutici
Small molecules binding G4C2 RNA
< foci < DPR
C9orf72 - Small Molecule Therapy
ALS/FTD: Precision Medicine
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Bertram and Tanzi, J Clin Inv 2005
Continuum
Ittner et al., 2015
FTD and ALS
FDA approved:- Riluzole (1995)- Edaravone (2017)
FDA approved:- none
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ALS-FTD as a historical continuum
FTLD
social language
non-fluent fluent
PNFA SD lvPPA
no cognitive impairment
PMA ALS PLS
ALS-PNFA ALS-SD
40-45%55-60%
10%
10%
bvFTD
cognitiveimpairment
bvFTD
FTD-MND
ALS-FTD
ALS-bi/ci
IRCCS Istituto Auxologico ItalianoCentro “Dino Ferrari”
Università degli Studi di Milano
Laboratory ofNeuroscience
Antonia RattiPatrizia BossolascoClaudia Colombrita
Lidia CovaValentina Gumina
Annamaria MaraschiFrancesca Sassone
Cinzia TilocaClara Volpe
Isabella Fogh London, UKNiccolò Mencacci Chicago, USA
Dept. Neurology-Stroke Unit
Laura AdobbatiLuca Campana
Andrea CiammolaBarbara CorràAlberto Doretti
Riccardo DoronzoAlessandra GnesaAnnalisa Lafronza
Carolina LombardiLuca Maderna
Stefano MessinaClaudia MorelliBarbara PolettiDavide Sangalli
Ignazio Keller SarmientoFederica SolcaNicola Ticozzi
Federico Verde
ICGEB Trieste
Francisco E. BaralleEmanuele Buratti
Fondazione IRCCS Istituto “Carlo Besta”
Cinzia GelleraFranco Taroni, Giuseppe Lauria
UMass Medical School
John E. Landers
Chi-Hong Wu, Jenni Adams, DesireeM. Baron, Daryl A. Bosco,
Robert H. Brown Jr.Claudia Fallini
Mayo Clinic Jacksonville, FL
Tania GendronLeonard Petruccelli
11/12/2017
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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
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
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
Maurizio Inghilleri
Fabio Blandini
Cristina Cereda
Mauro Ceroni
Cesare S. Silani
Un ulteriore ringraziamento a Pavia !
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