Update on spinocerebellar ataxias (SCAs) ?· •The spinocerebellar ataxias (SCAs) are a group of more…

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  • Update on spinocerebellar ataxias (SCAs)

    Thomas Klockgether

    EuroAtaxia Conference 2018 Frankfurt, 09.11.2018

  • • The spinocerebellar ataxias (SCAs) are a group of more than 40 autosomal dominantly inherited progressive ataxia disorders.

    • SCAs are rare diseases with an estimated prevalence of 5 : 100,000.

    • The clinical hallmark of SCAs is progressive loss of balance and coordination accompanied by slurred speech with an onset in adult life.

    • People affected by SCAs suffer substantial restrictions of mobility and communicative skills resulting in impaired quality of life.

    • Many SCAs lead to premature death.

    Spinocerebellar ataxias (SCA)

  • Genetic heterogeneity

    http://neuromuscular.wustl.edu/ataxia/domatax.html

  • Genetic heterogeneity

    Mutation Genotypes Prevalence Pathology Progression

    Translated CAG repeat expansion (polyglutamine)

    1,2,3,6,7,17 Common Often

    widespread Fast

    Untranslated repeat expansion

    8,10,12,31, 36,37

    Rare Cerebellar Slow

    Conventional Other Rare Cerebellar Slow

  • RNA toxicity

    Abnormal folding

    Cleavage

    Aggregation

    Pathogenesis of polyglutamine SCAs

    Abnormal interaction with multiple cellular proteins and processes

  • Gene knock-down

    Watts & Corey J Pathol 2012

  • McLoughlin et al. Ann Neurol 2018

    Dose-dependent suppression of mutant ATXN3

    Gene knock-down by antisense oligonucleotides

  • McLoughlin et al. Ann Neurol 2018

    Prevention of nuclear accumulation and aggregation of ATXN3

    Gene knock-down by antisense oligonucleotides

  • McLoughlin et al. Ann Neurol 2018

    Rescue of behavioral phenotype

    Gene knock-down by antisense oligonucleotides

  • • ASOs need to be repeatedly administered intrathecally at intervals of several months

    • ASO treatment approved for SMA, positive trial in HD

    • Active development programs by (big) pharmaceutical companies

    Gene knock-down by antisense oligonucleotides

  • SARA

    0 2 5 5 0 7 5 1 0 0

    0

    2 5

    5 0

    7 5

    1 0 0

    S A R A

    V A

    S

    2 0 4 0 6 0 8 0 1 0 0

    - 6 0

    - 4 0

    - 2 0

    0

    2 0

    4 0

    6 0

    8 0

    1 0 0

    S A R A

    V A

    S

    Schmitz-Hübsch et al. Neurology 2006;66:1717-20

    The Scale for the Rating and Assess- ment of Ataxia (SARA) is a novel clinical rating scale based on a standard neurological exam. SARA has 8 items (gait, stance, sitting, speech, finger-chase, nose-finger, fast alternating movements, heel-shin).

    Five validation trials in 617 ataxia patients (SCA, FRDA, sporadic ataxia) providing evidence for - reliability - validity - linearity - sensitivity to change

  • Training and education

    • SARA training tool

  • Jacobi et al. Lancet Neurol 2015;14:1101-8

    Linear mixed and pattern mixture modelling

    • SARA progression was linear in all genotypes.

    • SARA progression was fastest in SCA1, intermediate in SCA2 and SCA3, slowest in SCA6.

    Ataxia

    SCA1 SCA2

    SCA3 SCA6

  • Jacobi et al. Lancet Neurol 2013

    Pre-ataxia stage

    • RISCA is a longitudinal observational study of 300 non-ataxic first- degree relatives of SCA1, SCA2, SCA3 or SCA6 patients.

    • Genetic testing was done anonymously so that study participants and investigators were not aware of the individual genetic status.

    • SCA1, SCA2, SCA3 mutation carriers were enrolled on average 10 years before the expected ataxia onset, SCA6 carriers 20 years.

  • Jacobi et al. Lancet Neurol 2013

    non-carrier

    carrier

    SCA1 SCA2 SCA3 SCA6

    0 .0 0

    0 .2 5

    0 .5 0

    0 .7 5

    1 .0 0   

    C C

    F S

    .

    - 0 .5 0

    - 0 .2 5

    0 .0 0

    0 .2 5

    0 .5 0

      

    S C A 1 S C A 2 S C A 3 S C A 6

    S C

    A F

    I

    Baseline analysis showed minor differences in frequency of non- ataxia symptoms, clinical scales, functional performance and brain volumes between carriers and non- carriers.

    Pre-ataxia stage

  • • Within the observation period, 52% of SCA1 mutation carriers converted to manifest ataxia.

    • Clinical scales and test performance deteriorated in mutation carriers, but not non-carriers.

    Pre-ataxia stage

  • Regions with significant volume loss in non-ataxic SCA3 mutation carriers (compared to controls): 4th ventricle, pallidum, medulla oblongata, pons, mesencephalon)

    MRI marker

  • Regions with significant volume loss in ataxic SCA3 mutation carriers (compared to non-ataxic carriers): Cerebellar lobules

    MRI marker

  • International consortia

  • Despite extensive knowledge of clinical features and natural history of the common polyQ-SCAs, there remain major knowledge gaps and hurdles that preclude further progress towards effective therapies. Specifically,

    • it is not known how clinical features of SCA patients from different world regions compare to each other,

    • there is no detailed knowledge of the disease evolution in non- polyQ-SCAs,

    • imaging biomarkers have not yet been extensively validated,

    • biochemical markers are almost completely lacking, and

    • access to potential and well characterized study participants is limited.

    Clinical SCA Research - Challenges

  • SCA Global is conceived as a flexible and open research platform, with which we wish to pursue the following goals:

    • To better understand the manifestation, evolution and impact of the various SCAs

    • To develop and validate biomarkers which can be used in future interventional trials

    • To facilitate access to people with SCAs who are willing to participate in clinical trials

    SCA Global

    SCA Global has been launched during the NAF meeting in April 2018 in Philadelphia

  • Harmonization and standardization

    • Define a common standard for clinical assessment

  • Sampling Storage

    Harmonization and standardization

    • Define a common biosampling protocol

  • Harmonization and standardization

    • Define a common MRI protocol

    • Liaise with ENIGMA Ataxia (Ian Harding)

  • Harmonization and standardization

    • Define a common standard for consent forms

    • Create templates for data and material transfers agreements

  • Data acquisition

    • SCA Registry uses the same software as the Enroll-HD database (2mt Software (Ulm, Germany)

  • Data acquisition

  • • Transparent and democratic governance with participation of patient representatives

    • Accordance with high standards of data protection

    • Full and unlimited access of each investigator to own data and materials

    • Fair access of investigators to data and materials

    Basic principles

  • Governance

    • Coordinator

    • Steering committee NAF, EuroAtaxia, other lay organizations Clinical investigators (Europe, USA, South America, East Asia, Australia)

    • Business office

  • Agenda

    • Steering committee established

    • Website launched

    • Registration process in preparation

    • Organize 1st SCA Global Meeting, 27-29 Mar 2019, Las Vegas

    • Define standards (working groups)

    • Start data merging/acquisition

  • Website