Post on 23-Feb-2016
description
Ataxia research updateAtaxia 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
Energy production
Free radical damage
Iron mis-localisation
What happens in Friedreich’s ataxia?
Ataxia?Mutated
FrataxinGene
FrataxinProtein
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
Energy production
Free radical damage
Iron mis-localisation
Tackling Friedreich’s ataxia
MutatedFrataxin
Gene
FrataxinProtein
Antioxidants
IronChelators
Protein Therapy
Drugs to frataxin
Gene Therapy
Drugs to turnfrataxin gene on
Antioxidants
• ‘Mop up’ free radicals• Prevent damage from free radicals• Improve energy production in cell
MutatedFrataxin
Gene
FrataxinProtein
Energy production
Free radical damage
Iron mis-localisation
Antioxidants
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
MutatedFrataxin
Gene
FrataxinProtein
Energy production
Free radical damage
Iron mis-localisation
IronChelators
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
Drugs to frataxin
AtaxiaMutatedFrataxin
Gene
FrataxinProtein
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
AtaxiaMutatedFrataxin
Gene
FrataxinProtein
HDACi
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!