Transcript Dr Alison Stevenson`s presentation

Ataxia research update
Ataxia Ireland conference 28 Sep 2013
Dr Alison Stevenson
Overview
• Research developments in:
• Diagnosis
• Finding treatments in Friedreich’s ataxia
• Finding treatments in the cerebellar ataxias
• Moving from basic research to trials
• Funding research collaboratively
Ataxia UK and Ataxia Ireland joining forces
Funding from
Developments in diagnosis
• Ataxia has many causes
• Correct diagnosis is important – for prognosis,
management and to identify rare TREATABLE
forms
• Examples of treatable forms:
• Gluten ataxia
• Ataxia with CoQ10 deficiency
• Ataxia with Vitamin E deficiency
Improving diagnosis – genetic testing
• Many people do not have a specific
diagnosis; idiopathic, no known cause
• Genetic ataxias can be diagnosed by
genetic tests eg spinocerebellar ataxias
(SCAs); >36 types
• But tests for all are not available and are
performed on single genes at a time
Next generation sequencing for diagnosing
inherited ataxias
New genetic techniques developed that screen
more genes than was possible
eg: NGS of ataxia genes (Oxford)
eg: exon sequencing (Newcastle, London)
More accurate diagnoses
Gluten ataxia
• One year trial showed improvements in
ataxia with gluten-free diet
• Important to get early diagnosis
• Research from Sheffield Ataxia Centre
identified a new more sensitive test
Could lead to more people with a
diagnosis of gluten ataxia
Friedreich’s ataxia research developments
What happens in Friedreich’s ataxia?
Mutated
Frataxin
Gene
?
Frataxin
Protein
Energy
production
Free radical
Ataxia
damage
Iron
mis-localisation
Cell structural
changes
A new pathway for Friedreich’s ataxia
• Investigating new pathways in Friedreich’s
ataxia
• Changes in cell structure were seen – could
this be caused by something other than low
frataxin protein?
• PIP5K1-beta gene is ‘turned off’
• Encodes a protein that regulates cytoskeleton
• More studies required to fully understand this
discovery
Funding from
Tackling Friedreich’s ataxia
Antioxidants
Mutated
Frataxin
Gene
Drugs to turn
frataxin gene on
Gene Therapy
Energy
production
Frataxin
Protein
Free radical
damage
Iron
mis-localisation
Drugs to  frataxin
Protein Therapy
Iron
Chelators
Antioxidants
• ‘Mop up’ free radicals
• Prevent damage from free radicals
• Improve energy production in cell
Mutated
Frataxin
Gene
Antioxidants
Energy
production
Frataxin
Protein
Free radical
damage
Iron
mis-localisation
Idebenone
• Similar to CoQ10
• A powerful antioxidant
• Clinical trials in USA and Europe showed
trends towards improvements but no
significant changes
• Data is insufficient to licence idebenone for
Friedreich’s ataxia
• Will PROTI study show that taking
idebenone can be beneficial?
Future of idebenone?
• Awaiting results of PROTI study
• In Canada, sale of idebenone (Catena)
has been discontinued
• Available on a named patient basis in
the UK
Other antioxidants
• Vitamin E and CoQ10
• Possibly beneficial to people who have low levels
• A0001
• Well tolerated; some neurological symptoms improved
• More studies needed
• EPI-743
• Recruiting in the USA for a Phase II trial (Edison)
• OX-1
• Phase II clinical trial? (Viropharma)
• EGb761
• No published data
Other antioxidants (contd)
• Pioglitazone (Actos)
• Prescribed for type II diabetes
• Enhances antioxidant response; improves
energy production; may influence frataxin levels
• 2 year trial; on-going
• Resveratrol
• Neuroprotective; increases frataxin levels
• Pilot study; 2 different doses for 12 weeks, open
label
• Measuring frataxin levels, oxidative stress, ataxia
and heart function
• Results show some promise so other trial
planned
Iron chelators
• Iron chelators ‘mop up’ excess iron
• Hypothesis: iron chelators will mop up
excess iron from mitochondria and
improve energy production
• Caution: not to deplete iron from other
parts of the cell
Mutated
Frataxin
Gene
Energy
production
Frataxin
Protein
Free radical
damage
Iron
mis-localisation
Iron
Chelators
Deferiprone clinical trials
• Deferiprone
• Long-term safety, tolerability and efficacy
• Awaiting results
• Deferiprone & idebenone
• Generally well-tolerated
• Mixed results for efficacy
• Deferiprone, idebenone & riboflavin
• Possibly some neurological and heart
benefits; inconclusive results
• 4 of 13 participants withdrew (adverse effects)
• More studies needed; monitoring and
regular health checks important
Drugs to increase frataxin: EPO-alpha
• Erythropoietin (EPO) - hormone that
promotes red blood cell production
• EPO-alpha – for anaemia, cancer and
other critical illnesses
• Neuroprotective; increases frataxin
protein – mode of action is unknown
Mutated
Frataxin
Gene
Frataxin
Protein
Drugs to  frataxin
Ataxia
EPO-alpha clinical trial
• Phase II randomised double-blind
placebo-controlled trial
• Long term effects; exercise capacity,
safety and tolerability
• Recruiting in Italy
• Caution with EPO; it can:
• Increase red blood cell production
• Lower iron levels
Interferon gamma
• Naturally occurring molecule; involved
in the body’s immune response
• Licensed for two other rare conditions
• Increases frataxin in cells and mice
• Two human clinical trials:
• Italy – safety of 3 escalating doses (adults)
• USA – identifying safe dose for children
• Orphan drug status registered
HDAC inhibitors
• Histone deacetylase inhibitors (HDCAi)
• Switch frataxin gene back on
Mutated
Frataxin
Gene
HDACi
Frataxin
Protein
Ataxia
RG2833
• Developed by researchers at Scripps
Research Institute and Repligen
• Phase I pilot study in Turin completed;
some preliminary results:
– Well tolerated; no severe adverse events
– All participants completed the trial
– Increased frataxin gene activity
– Proof of concept achieved; HDACi can
‘switch on’ the frataxin gene
• Developing a better version of RG2833
Funding from
Nicotinamide / Vitamin B3
• Increases frataxin levels in cells from
people with Friedreich’s ataxia
• Good safety profile
• Trial is looking at safety of the
compound and its ability to increase
frataxin levels
• Trial is on-going
Funding from
Summary of Friedreich’s ataxia clinical trials
• Awaiting results
• Idebenone, pioglitazone, resveratrol,
EGb761
• Deferiprone
• RG2883
• On-going trials
• EPI-743
• EPO-alpha, interferon-gamma, nicotinamide
• Future trials
• OX-1
Cerebellar ataxia research developments
The cerebellum is a processing centre
• Receives input from and
send messages to other
parts of the brain and
central nervous system.
• Important in the control
of balance, coordination
and movement.
• Compromised function =
cerebellar ataxia
cerebellum
Causes of cerebellar ataxia
• Over 60 types of cerebellar ataxia
• Many have a genetic cause
• These are classified according to the
gene that is mutated
• eg >36 SCAs
Finding treatments: a drug screen for SCA3
• Genetically modified worms (C elegans)
develop symptoms of SCA3
• Used to screen 2,800 FDA-approved and
off-patent drugs
• 30 ‘hits’
• 2 most promising ‘hits’ being tested in a
mouse model of SCA3
Exon-skipping for the ataxias
• A new technique to eliminate the effects
of mutated parts of genes and prevent
toxicity
• Tested for SCAs 3, 7, 17 and DRPLA
• SCA3:
• Good skipping of faulty part of gene
• Non-toxic protein produced
• More testing in SCA3 animal models
required
• Clinical trials for Duchenne muscular
dystrophy
Clinical trials: Riluzole
• Approved treatment for amyotrophic
lateral sclerosis
• Rationale – riluzole will regulate nerve
impulses in the cerebellum
• Small 8 week trial showed some
improvements in neurological symptoms
• Follow-up study:
•
•
•
•
60 people with hereditary ataxia
12 months
Double-blind, placebo-controlled trial
Recruiting in Italy
Varenicline
• Anti-smoking medication (Champix)
• Small, 8 week trial showed some cautiously
positive results in people with SCA3
• Some walking and standing improvements
but overall not significantly better than the
placebo group
• More studies over longer time periods are
required
CoQ10
•
•
•
•
Naturally occurring antioxidant
Deficiency can cause ataxia
Inconclusive results from clinical trials
New diagnostic test developed; will also
be useful for measuring levels in trials
• CoQ10 testing is available
Other drugs in clinical trials
• Dalfampridine (4-aminopyridine, Ampyra)
• For EA2; USA, invitation only
• For gait in SCA; USA, recruiting
• Lithium for SCAs 1, 2, 3
• Trials completed
• Awaiting results
• High dose immunoglobulin
• For spinocerebellar degeneration
• KP-0373
• For spinocerebellar degeneration
Summary of cerebellar ataxia research
developments
• Clinical trials - awaiting results
• Lithium for SCAs 1, 2, 3
• Clinical trials - on-going
• Riluzole for hereditary CA
• Dalfampridine for EA2
• Dalfampridine for SCAs
• Alleviating symptoms
• Move ‘n’ fun
• Finding treatments - research
continues
Alleviating symptoms: Move ‘n’ fun
• Aim: to assess coordinative training in
children with ataxia
• Based on benefits from similar training in
adults
• Training will use videogames controlled
by full body movements and can be done
at home
Funding from
Results are promising
• Tested 10 children with progressive
ataxias
• 8 week programme
• Assessed before and after treatment
• Found improvements in ataxia
• ataxia rating scale (SARA –especially
posture)
• Quantitative movement analysis (decrease in
step variability, lateral sway and errors in goal
directed leg placements)
Challenges for clinical trials
• Ataxia is not a stable condition
• Measuring changes is difficult
• No change can be an improvement for a
progressive condition
• Numbers of people to recruit to clinical
trials is limited
• Treatment may be effective for a subset of
people
• Intellectual property
• Developing a new drug, even if everything
goes well, take a long time
In our favour…
• More drugs in trials than ever before
• Strong, collaborative research community
• Large European research consortia
working on Friedreich’s ataxia and the
cerebellum
• Dedicated supporters
• Fundraising
• Participating in research projects
• Collaborations with other ataxia
organisations
• Pharmaceutical companies eg Pfizer
Thank-you for listening!