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

Mutated
Frataxin
Gene
Frataxin
Protein
?
Energy production
Ataxia damage
Iron mis-localisation
Cell structural changes

• Investigating new pathways in Friedreich’s ataxia
• Changes in cell structure were seen – could this be caused by something other than low frataxin protein?
• PIP5K1beta gene is ‘turned off’
• Encodes a protein that regulates cytoskeleton
• More studies required to fully understand this discovery
Funding from

Antioxidants
Mutated
Frataxin
Gene
Frataxin
Protein
Energy production
Free radical damage
Iron mis-localisation
Drugs to turn frataxin gene on
Gene Therapy
Drugs to
 frataxin
Protein Therapy
Iron
Chelators

Antioxidants
• ‘Mop up’ free radicals
• Prevent damage from free radicals
• Improve energy production in cell
Antioxidants
Mutated
Frataxin
Gene
Frataxin
Protein
Energy production
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
Energy production
Mutated
Frataxin
Gene
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
Ataxia
Drugs to
 frataxin

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

• 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

• Histone deacetylase inhibitors (HDCAi)
• Switch frataxin gene back on
Mutated
Frataxin
Gene
Frataxin
Protein
Ataxia
HDACi

• 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

• 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

• 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

• 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

• 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

• 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

• 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!