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Duchenne Muscular Dystrophy – a severe muscle wasting disease
Dr T Willis Paediatric Neurologist, RJAH and BCH.
Dr D Willis Severn Hospice, Telford.
Caused by an out of frame mutation in the dystrophin gene
Absence of dystrophin in muscle fibres
prevalence 1/3500
newborn boys
Duchenne Muscular Dystrophy
Progressive symmetrical muscular weakness Proximal > distal Calf hypertrophy Symptoms < 5 years Wheelchair < 13 years (without treatment) Respiratory and Cardiac involvement Behavioural problems/ASD Learning difficulties
Elfux/influx of
Proteins/growth factors
Muscle fibres
hypertrhophy
Genetic defect
Loss of membrane integrity
Fibrosis
Necrosis
Loss of muscle mass
Muscular Dystrophy
Duchenne Muscular Dystrophy: current treatments
Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
Bone health and management
Psychological support
Duchenne Muscular Dystrophy: current treatments
Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
Corticosteroids
Duchenne Muscular Dystrophy: current treatments
Pharmacological treatments
Prednisolone/Prednisone 0.75mg/kg/day
Deflazacort 0.9mg/kg/day
Delays loss of ambulation to age 11-15 years
(Cochrane review, AAN, ENMC) Manzur et al. “Glucocorticoids dor Duchenne muscular dystrophy” Cochrane Database Syst Rev. 2008
Facilitates development of additional skills e.g. Jumping, hopping running, riding a bike
Reduces likelyhood of spinal surgery from 90% to 10%
Maintains respiratory function delaying
need for assistive ventilation
Side effects:
Weight gain
Behaviour problems
Cushingoid appearance
Vertebral fractures
Short stature
Delayed puberty
Cataracts
Hypertension
GI bleeding
Diabetes
Duchenne Muscular Dystrophy: Impact of steroids
Are significant
Require proactive management • Behavioural guidance • Prophylaxis/treatment of
osteoporosis • Regular follow up (BP, glycosuria,
eye check, physical exam)
Muscular Dystrophy: current treatments
Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
Muscular Dystrophy: current treatments
Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
Single most important impact
on natural history of DMD
Duchenne Muscular Dystrophy: Respiratory care
1)Timely and appropriate assessment
2) Prevention 3) Active interventions
Ventilatory support (NIV, BiPap)
Cough Assist Machine
Regular (6 months- yearly) FVC check
Overnight studies- oxygen
Muscular Dystrophy: current treatments
Pharmacological treatments
Treatment of complications
Respiratory care
Cardiac management
Orthotic and orthopaedic approach
Feeding management
Duchenne Muscular Dystrophy: Cardiac treatment
1) Timely and appropriate assessment 2) Prevention 3) Active management
ACE-inhibitors Steroids?
ACE-inhibitors + beta-blockers
ECG and Echo At diagnosis Before any surgery Every two years to age 10 Annually after age 10
Respiratory support is proven to improve life expectancy with maintenance of a good quality of life
Cardiac surveillance and treatment is likely to have similar benefits
DMD is a treatable disease Predictable complications in different systems
Steroids prolong ambulation and delay the onset of other complications
In conjunction with physiotherapy regimes
Modification of the mutation
(Exon skipping, stop codon suppression)
Gene transfer
Cell therapies
Upregulation of alternative
proteins
Increase in muscle bulk
Addressing downstream
pathology
DNA
RNA
Protein
Gene Addition e.g. microdystrophin via viral vector. Cell therapy.
Modify RNA e.g. exon-skipping
Modify translation e.g. gentamycin PTC 124 (ataluren)
“Genetic” therapies
Large deletions and duplications
Splice site mutations
Small deletions and insertions
Nonsense mutations
Missense mutations
From Roberts at al, 1994
Types of mutations associated with DMD
Most mutations disrupt the open reading frame leading to a failure to fully translate the mRNA and produce a functional protein
Mendell et al, 2010
LGMD2D Gene therapy clinical trial
Potential to improve muscle regeneration and restore dystrophin but will not make new muscle per se
1990s – myoblast transplants – unsuccessful
Trembley (Canada) continuing with a Phase 1/2 clinical trials with local delivery to a specific muscle.
Mesoangioblast trial run by Guilio Cossu in Italy
Stem cell trials (Phase 1/2) ongoing in Turkey and India.
Cardiosphere derived cells delivered via intracoronary infusion (Capricor, USA, Phase 1/2)
Two chemistries taken to clinical trial – 2OmePS and PMO. Evidence of clinical benefit – arresting the progression of the disease for boys eligible for exon 51 skipping.
Other exon targets current in clinical trial (44, 45, 53).
Other antisense reagents:
Cell penetrating peptides linked to PMO
TricycloDNA oligonucleotides
17 years of research & development
750+ healthy volunteers/patients exposed/treated and
~900 patient-years of treatment
Safety profile: Generally well tolerated
Phase 2a: Dystrophin expression demonstrated
Phase 2b: Clinically meaningful benefit in 6MWT/Natural History data
Phase 3: ACT DMD fully enrolled with data expected Q4 2015
EMA granted marketing authorisation approval for ambulatory nmDMD patients
aged 5 years and older – July 2014
24
98–2003 2008 2009 2011 2012 2013 2010 2007 2005
Phase 2a (004) 38 nmDMD patients
2006 2004
Phase 1 62 healthy
males
2014
Phase 2b (007) 174 nmDMD patients
EMA DMD draft guidelines
Initial natural history
publications
ataluren discovery
EMA approval of ataluren
2015
Phase 3 (020) 220 nmDMD
patients
Slide 25
~13% of boys have DBMD due to a nonsense mutation
Incomplete dystrophin
Nonsense (Premature
Stop) Codon
Normal Stop
Codon
Dystrophin mRNA
Slide 26
~13% of boys have DBMD due to a nonsense mutation
Incomplete dystrophin
Nonsense (Premature
Stop) Codon
Normal Stop
Codon
YIELD
Full-length
dystrophin
Normal Stop
Codon
Nonsense (Premature
Stop) Codon
Dystrophin mRNA
Ataluren induces full-length protein production
Dystrophin mRNA
Up-regulation of utrophin to treat DMD. Increasing muscle mass. Inhibiting the pathological process. Improving the blood supply to muscles Nutritional supplements. All the above use compounds that can be
delivered systemically thus offering the promise of treating all affected muscles.
Many compounds are already in use in man.
Contractile apparatus
Dystrophin or
Utrophin
Costamere
Section through a muscle fibre Finite number of springs
Finite number of binding sites Contraction and relaxation stress transmitted through costamere anchor sites
Muscle fibre membrane
No springs Structural failure
No dystrophin (Duchenne) Structural failure
Fewer springs Still functional but lower weight capacity
Less dystrophin (Becker) Still functional but lower stress tolerance
Utrophin similar to dystrophin but does not localise nNOS Expression of utrophin developmentally precedes dystrophin Can correct mdx mouse SMT C1100 : Utrophin Inducer for DMD
Currently in Phase 1b clinical trial (Summit). Biglycan: Stabilises utrophin at the muscle membrane (Tivorsan)
Corticosteroids – current standard of care where tolerated but have significant side effects
Potential alternatives (most act by inhibiting NFkB): ◦ Halofugionone (HT-100 Phase ½, Akashi Therapeutics) ◦ CAT-1000 (Phase ½, Catabasis) ◦ VBP-15 (about to enter trial, ReveraGen)
◦ Nemo-binding domain (NBD) peptide ◦ And others……..
Myostatin is a negative regulator of muscle mass Release of soluble form of the Activin IIB receptor to block myostatin signaling (Acceleron - ACE-031). Trial stopped because of bleeding. Antibody to block myostatin binding. Pfizer PF-06252616 (phase 1/2). Adnectin to block myostatin. Bristol-Myers Squib BMS-986089 (Phase 1/2) Other strategies: Propeptide blocker, Inhibition of myostatin production (siRNA)
Many different treatment strategies exist
Many different companies undertake efforts to develop successful treatment for DMD
To date, still no treatment available on the market
New therapies for DMD: translational research
Although new research into possible molecular treatments for DMD is at an exciting stage, currently compliance with internationally agreed standards of care remain the highest priority in prolonging survival and increasing quality of life
Addressing the lack of “trial culture” in NMD
Patient identification – importance of national and international registries
Managing expectations - the ethical environment for trials
High technology and high costs
Working with pharmaceutical companies
Precise molecular diagnosis
Understand the natural history of the condition
Define outcome measures
Consistency of care and management (Standards of care)
Awareness that DMD is a systemic disease and very much an adult disease
Paed vs adult
Hospices not taking them
Discuss pall care at diagnosis?
It’s a different disease now
Pain is an issue in the late stage
Control
Negotiation is a large part of the consultation process
Right to have family is an issue- more than my experience of normal pall care
