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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

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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

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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

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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

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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 !