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Current and planned clinical Current and planned clinical research in DMDresearch in DMD
Newcastle Collaborative workNewcastle Collaborative workDr Michelle EagleDr Michelle Eagle
Research Practitioner Research Practitioner PhysiotherapistPhysiotherapist
Newcastle Muscle CentreNewcastle Muscle Centre
Where do we need more evidence in Where do we need more evidence in DMD?DMD?
How do we best use the drugs we How do we best use the drugs we have already got?have already got? Phase III clinical trialsPhase III clinical trials Corticosteroids, cardioprotective Corticosteroids, cardioprotective
medicationmedication How do we test new compounds?How do we test new compounds?
Phase I/II clinical trialsPhase I/II clinical trials Antisense oligonucleotide treatment, Antisense oligonucleotide treatment,
PTC 124 etcPTC 124 etc Myostatin inhibition?Myostatin inhibition?
Medicine cannot be ruled by anecdoteMedicine cannot be ruled by anecdote
Phase III clinical trials in DMDPhase III clinical trials in DMD FOR- DMD: international trial of steroid FOR- DMD: international trial of steroid
dosage regimens, seeking NIH fundingdosage regimens, seeking NIH funding 300 patients, 14 different countries300 patients, 14 different countries 3 years + follow up (+2)3 years + follow up (+2) Three different steroid regimensThree different steroid regimens
Continuous deflazacort or prednisoloneContinuous deflazacort or prednisolone Intermittent predisoloneIntermittent predisolone
Which one gives the best functional gain and is Which one gives the best functional gain and is most satisfactory to take?most satisfactory to take?
What is the relative burden of side effects?What is the relative burden of side effects?
The ultimate test of the impact the natural The ultimate test of the impact the natural course of the disease, and the burden of course of the disease, and the burden of side effects, will be over a longer period. side effects, will be over a longer period.
The initial project will be embedded within The initial project will be embedded within a 10 year follow up study for which further a 10 year follow up study for which further funding will be sought in due course. funding will be sought in due course.
It will be possible to address issues It will be possible to address issues concerning standards of care in DMD and concerning standards of care in DMD and the management of CS-associated side the management of CS-associated side effects, effects,
as well as develop a resource to study the as well as develop a resource to study the pharmacogenetic response to CS pharmacogenetic response to CS treatment and the mode of action of CS in treatment and the mode of action of CS in improving strength in DMD. improving strength in DMD.
Table 1 Participants in international DMD treatment Table 1 Participants in international DMD treatment trialtrial
Belgium (for the Belgian network)Belgium (for the Belgian network) Brussels: Peter van de Bergh (6)Brussels: Peter van de Bergh (6) CanadaCanada Shannon Venance (3)Shannon Venance (3) FinlandFinland Helsinki: Helena Pihko (10)Helsinki: Helena Pihko (10) FranceFrance Lyon: Carole Berard (5)Lyon: Carole Berard (5) Germany (for the German MD-Net)Germany (for the German MD-Net) Rudolph Korinthberg (50)Rudolph Korinthberg (50) Italy (co-ordinator, C. Angelini)Italy (co-ordinator, C. Angelini) Bologna: Marcello Villanova (20)Bologna: Marcello Villanova (20) Messina: Guiseppe Vita (5)Messina: Guiseppe Vita (5) Naples: Giovanni Nigro (20)Naples: Giovanni Nigro (20) Padova: Corrado Angelini, Roberto Padoan (8)Padova: Corrado Angelini, Roberto Padoan (8) Pavia: Angela Berardinelli (3)Pavia: Angela Berardinelli (3) Rome: Enzo Ricci, Enrico Bertini, Eugenio Mercuri (15)Rome: Enzo Ricci, Enrico Bertini, Eugenio Mercuri (15) Netherlands (for the VSN network)Netherlands (for the VSN network) Imelda de Groot, Anneke van der Kooi (20)Imelda de Groot, Anneke van der Kooi (20) Scandinavian network (for the Scandinavian network, co-Scandinavian network (for the Scandinavian network, co-
ordinator Thomas Sejersen) ordinator Thomas Sejersen) Sweden/ Denmark/NorwaySweden/ Denmark/Norway Birgit Steffensen, Thomas Sejersen, Jas Rahbek, Magnhild Birgit Steffensen, Thomas Sejersen, Jas Rahbek, Magnhild
Rasmussen (25)Rasmussen (25) UK (North Star network)UK (North Star network) Birmingham: Helen Roper (8)Birmingham: Helen Roper (8) Bristol: Phil Jardine (5)Bristol: Phil Jardine (5) Cardiff (Welsh network): Louise Hartley, Cathy White, Jane Cardiff (Welsh network): Louise Hartley, Cathy White, Jane
Fenton-May (10)Fenton-May (10) Dundee: Karen Naismith (3)Dundee: Karen Naismith (3)
Leeds: Anne- Marie Childs (12)Leeds: Anne- Marie Childs (12) London (Hammersmith): Francesco Muntoni, Adnan Manzur London (Hammersmith): Francesco Muntoni, Adnan Manzur
(20)(20) Manchester: Imelda Hughes (8)Manchester: Imelda Hughes (8) Newcastle: Katharine Bushby, Volker Straub (6)Newcastle: Katharine Bushby, Volker Straub (6) Oswestry: Ros Quinlivan (6)Oswestry: Ros Quinlivan (6) Sheffield: Peter Baxter (4)Sheffield: Peter Baxter (4) Southampton: Neil Thomas (4)Southampton: Neil Thomas (4) USAUSA Baltimore: Kathryn Wagner (6)Baltimore: Kathryn Wagner (6) Boston: Basil Darras (6)Boston: Basil Darras (6) New York City: Petra Kaufmann (17)New York City: Petra Kaufmann (17) Columbus: Jerry Mendell (20)Columbus: Jerry Mendell (20) Kansas City: Richard Barohn (10)Kansas City: Richard Barohn (10) New Mexico: Leslie Morrison (5)New Mexico: Leslie Morrison (5) Oregon: Edward Cupler (8-10)Oregon: Edward Cupler (8-10) Rochester: Richard Moxley, Emma Ciafaloni (5)Rochester: Richard Moxley, Emma Ciafaloni (5) Salt Lake City: Kevin Flanigan (20)Salt Lake City: Kevin Flanigan (20) San Antonio: Carlayne Jackson (6)San Antonio: Carlayne Jackson (6) Los Angeles: Melissa Spencer (20-25)Los Angeles: Melissa Spencer (20-25) Other investigators are committed to the project and Other investigators are committed to the project and
will be called upon as necessary.will be called upon as necessary. Paris: Brigitte EstournetParis: Brigitte Estournet Spain (for the Spanish Neuropaediatric network)Jaume Colomer Spain (for the Spanish Neuropaediatric network)Jaume Colomer Switzerland (for the Swiss neuropaediatric network) Pierre Switzerland (for the Swiss neuropaediatric network) Pierre
Jeannet Jeannet London (Guys):Heinz Jungbluth and Elizabeth WraigeLondon (Guys):Heinz Jungbluth and Elizabeth Wraige Miami: Walter BradleyMiami: Walter Bradley Philadelphia: Carsten BonnemannPhiladelphia: Carsten Bonnemann
Why do we need this kind of Why do we need this kind of trial?trial?
Because there is great variation in practice Because there is great variation in practice of use of corticosteroids in DMDof use of corticosteroids in DMD
Because there are no published long term Because there are no published long term controlled studies on the regimens in controlled studies on the regimens in common usecommon use
Because steroid treatment in ambulant Because steroid treatment in ambulant patients with DMD has become the “gold patients with DMD has become the “gold standard” against which other treatments standard” against which other treatments will need to be testedwill need to be tested
Steroids and non-Steroids and non-ambulatory boys with ambulatory boys with
DMDDMD
Steroids and respiratory Steroids and respiratory managementmanagement Continuous steroids improve the FVC) in Continuous steroids improve the FVC) in
ambulant boys with DMD. In boys taking ambulant boys with DMD. In boys taking continuous DFZ FVC was preserved to over 1 continuous DFZ FVC was preserved to over 1 litre aged 22. litre aged 22.
FVC in litres in age matchedboys with DMD. 18 months of
steroid treatment v notreatment
FVC untreated FVC treated1.00
1.25
1.50
1.75
litre
s
% FVC in age matched boyswith DMD. 18 months of steroid
treatment v no treatment
untreated treated60
70
80
90
100
per
cen
tag
e F
VC
Of boys aged 8.7 & 8.6 years mean FVC in the treated group was 1.5 litres (88% predicted) compared with 1.29litres (70% predicted) in the untreated group. % FVC was significantly greater in treated boys (p=0.0014)
12 13 14 15 16 17 180.00
0.25
0.50
0.75
1.00
1.25
1.50
chest infection
fatigue, needsto lie downduring day,difficulty gettinggo to sleep
weightloss
afraid ofgoing tosleep
FV
C
Why is the FVC so important?Why is the FVC so important?
8 10 12 14 16 18 20 22 24 260
1
2
NV introduced
SpinalSurgery
Age
lossofambulation
Vit
al c
apac
ity
Deteriorating FVC correlates with increasingRespiratory symptoms
Need for ventilationCan be predicted by correlating symptoms and FVC
FVCFVC
96 108 120 132 144 156 168 180 192 204 216 228 240 252 264 276 288 300 312 3240.0
0.5
1.0
1.5
2.0
2.5
no 25
no 168
no 134
no 37
no 124
no 2
no 68no 57
no 152 no 53
no 114 no 110no 145
no 99 no 4
no 175
no 35
no 160no 75
no 131
no 132 no 126
no 42
age in months
FV
C
Prognosis is improvedthe older the boy is when he reaches his peakFVC and the higher that peak is.
Non-ambulant steroid trialNon-ambulant steroid trialFunded by PPUKFunded by PPUK
Steroids are known to help improve Steroids are known to help improve strength in ambulant boys but what strength in ambulant boys but what about those who are unable to walk?about those who are unable to walk?
AimAim To evaluate the impact of steroids on forced To evaluate the impact of steroids on forced
vital capacity in ambulant and non-ambulant vital capacity in ambulant and non-ambulant boys with Duchenne muscular dystrophy (DMD).boys with Duchenne muscular dystrophy (DMD). Improving the peak FVC and/or maintaining the FVC Improving the peak FVC and/or maintaining the FVC
could delay the need for nocturnal ventilation and could delay the need for nocturnal ventilation and improve life expectancy.improve life expectancy.
Also wanted to see if there was any Also wanted to see if there was any improvement in functional ability and muscle improvement in functional ability and muscle strengthstrength
Open label pilot studyOpen label pilot study
• prednisolone at 0.75mg/kg/day was prednisolone at 0.75mg/kg/day was prescribed for non ambulant boys. prescribed for non ambulant boys.
• A pre-treatment assessment period of A pre-treatment assessment period of three months was followed by 6 months three months was followed by 6 months treatment and then a further three treatment and then a further three months without treatment.months without treatment.
• DEXA, ECHO, overnight oxymetry, manual DEXA, ECHO, overnight oxymetry, manual muscle testing, functional testing, well muscle testing, functional testing, well being scales assessed 6 weeklybeing scales assessed 6 weekly
PatientsPatients• 48 not ventilated patients were identified 48 not ventilated patients were identified
from our clinic populationfrom our clinic population• Two were excluded with severe Two were excluded with severe
cardiomyopathy, 4 patients approaching cardiomyopathy, 4 patients approaching ventilation, 2 very obese and one diabetic ventilation, 2 very obese and one diabetic were also excluded. were also excluded.
• 39 patients were asked to participate and 39 patients were asked to participate and 12 agreed. One patient died suddenly 12 agreed. One patient died suddenly after the first baseline assessment. after the first baseline assessment.
• Data collection is unfinished in four Data collection is unfinished in four patientspatients
FVC deteriorated in all patients FVC deteriorated in all patients prior to starting steroids prior to starting steroids
FVC improved with treatment FVC improved with treatment to more than the baseline level to more than the baseline level except those whose pre except those whose pre treatment FVC was below one treatment FVC was below one litre (although they still litre (although they still improved) improved)
FVC deteriorated to below the FVC deteriorated to below the baseline when treatment was baseline when treatment was stoppedstopped
mean FVC from three monthspre treatment to 18weeks of
treatment at 6 weekly intervals
pre
3mon
ths
pre
6 wee
k
6wee
ks R
x
12 w
eeks
Rx
18 w
eeks
Rx
24 w
eeks
Rx
6 wee
ks p
ost R
x
12 w
eeks
pos
t Rx
0
1
2
time
FV
C (
litr
es)
Preliminary Results
11 12 13 14 150.0
0.5
1.0
1.5
startedsteroids
stoppedsteroids
ventilatednocturnally
age
FV
C
Figure 3c
28.0 28.5 29.0 29.5 30.0 30.5 31.0 31.51.5
2.0
startedsteroids
stoppedsteroids
Figure 3a
Age
FV
C li
tres
18.0 18.5 19.0 19.5 20.0 20.5
1
2
startedsteroids
stoppedsteroids
Figure 3b
age
FV
C l
itre
s
Muscle strength and Muscle strength and Functional AbilityFunctional Abilitymuscle strength
3/12
pre
Rx
start
stero
ids
6/52
Rx
12/5
2 Rx
18/5
2 Rx
24/5
2 Rx
30/5
2 no
Rx
0
25
50
75
time
% s
core
EK Functional scores pre andpost steroid
3/12
pre
Rx
start
stero
ids
6/52
Rx
12/5
2 Rx
18/5
2 Rx
24/5
2 R
x
6/52
post
Rx0
10
20
timesc
ore
Eight patients have completed 6 months on steroid Rx and five have Eight patients have completed 6 months on steroid Rx and five have requested to restart steroids. requested to restart steroids. Reasons include deteriorating motor ability, weight loss, recurrence of Reasons include deteriorating motor ability, weight loss, recurrence of hip pain and loss of ability to lift arms when steroids were stopped.hip pain and loss of ability to lift arms when steroids were stopped.
SummarySummary• FVC improves over a 6 months period whilst taking steroids FVC improves over a 6 months period whilst taking steroids
and deteriorates when steroids are stopped. and deteriorates when steroids are stopped.
• The peak FVC may not be reached within 6 months as some The peak FVC may not be reached within 6 months as some patients were still improving at the end of a 6 month trial. patients were still improving at the end of a 6 month trial.
• Patients with an FVC below 1 litre do not show as much Patients with an FVC below 1 litre do not show as much benefit as those with an initial FVC over 1 litre and may benefit as those with an initial FVC over 1 litre and may deteriorate rapidly when steroids are withdrawn. deteriorate rapidly when steroids are withdrawn.
• There appears to be a stabilisation of strength over a 6 month There appears to be a stabilisation of strength over a 6 month period.period.
Functional improvement lags a little behind the stabilisation in Functional improvement lags a little behind the stabilisation in powerpower
Some non-ambulant patients benefited from increased Some non-ambulant patients benefited from increased weight but weight gain may be an undesired side effect. weight but weight gain may be an undesired side effect. There were no reported behavioural or emotional There were no reported behavioural or emotional disturbances over a 6 month period. Acne was a problem in 2 disturbances over a 6 month period. Acne was a problem in 2 patients.patients.
Preliminary ConclusionsPreliminary Conclusions
Steroids should be considered for Steroids should be considered for non-ambulant patients with DMDnon-ambulant patients with DMD
Care should be taken if steroids are Care should be taken if steroids are stopped as the FVC will deterioratestopped as the FVC will deteriorate
Further research is required to Further research is required to determine optimum dose and side determine optimum dose and side effect/efficacy balanceeffect/efficacy balance
Heart protection in DMDHeart protection in DMD
Scale & Implications of Cardiac Scale & Implications of Cardiac InvolvementInvolvement
Nature of Nature of cardiac cardiac
involvemeninvolvementt
%%
Cardiac Cardiac involvemeinvolveme
ntnt
Age of Age of onsetonset(years)(years)
Cardiac Cardiac deathdeath
DMDDMD ECGECG
DCM / HCMDCM / HCM> 90%> 90%
> 90%> 90%from 6 from 6
by 12 by 12 10-20%10-20%
BMDBMD ECGECG
DCM / HCMDCM / HCM> 90%> 90%
~ 65%~ 65%variablevariable 50%50%
Female Female CarriersCarriers
DCMDCM 7-11%7-11% variablevariable ??????
CardiomyopathyCardiomyopathy- - dilated (segmenatal or global)dilated (segmenatal or global)- - hypertrophichypertrophic
Electrical problemsElectrical problems- ECG changes - ECG changes (‘electropathy’)(‘electropathy’)-- Ventricular arrhythmias Ventricular arrhythmias
Prophylactic therapy of LV DysfunctionProphylactic therapy of LV DysfunctionThe Evidence-base in DMD ?The Evidence-base in DMD ?
♣♣ Detailed descriptions of progressive LV Detailed descriptions of progressive LV deteriorationdeterioration
♣♣ Extensive evidence of ACE & beta-blocker benefit Extensive evidence of ACE & beta-blocker benefit in LV dysfunction and heart failure of other in LV dysfunction and heart failure of other aetiologies.aetiologies.
♣♣ Anecdotes of improvements in DMDAnecdotes of improvements in DMD- in symptoms of LVF- in symptoms of LVF
♣♣ Newcastle clinic results of treating boys with Newcastle clinic results of treating boys with progressive asymptomatic heart dysfunctionprogressive asymptomatic heart dysfunction
Cardiac involvement in DMD – when to Cardiac involvement in DMD – when to interveneintervene
0
20
40
60
80
100
0 6 12 18 24 30 36
LV
Fu
nct
ion
Onset of Onset of LVF LVF
symptomssymptoms
Age (years)
Normal Normal rangerange
Effect of treating asymptomatic LV Effect of treating asymptomatic LV dysfunctiondysfunction
Patients started >= 2000
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
Age 1
3
Age 1
4
Age 1
5
Age 1
6
Age 1
7
age
18
age
19
age
20
age
21
age
22
age
23
age
24
AinsleyM
Winterbone
Fisher
AinsleyB
LVEF%LVEF%
70%
60%
50%
40%
30%
20%
10%
0%
13 14 15 16 17 18 19 20 21 22 23 24 25
Age Age (years)(years)
Stabilising Effects of ACE & BB therapy
‘‘Effect of Perindopril on the Onset & Progression of Effect of Perindopril on the Onset & Progression of Left Ventricular Dysfunction in Duchenne Muscular Left Ventricular Dysfunction in Duchenne Muscular
Dystrophy’Dystrophy’LV assessed:LV assessed: 6, 12, 18, 36 & 60 months6, 12, 18, 36 & 60 months
End-points:End-points: Primary: Primary: LVEF (radionuclide) < 45%LVEF (radionuclide) < 45%
Secondary:Secondary: Tolerability of perindoprilTolerability of perindopril
Duboc et al - J Am Coll Cardiol - 2005, 45:855-7
Timeframe Timeframe [n][n]
PerindoprilPerindopril PlaceboPlacebo pp
Baseline Baseline [60][60] 00 00 NSNS
36 months 36 months [60][60]
End of phase IEnd of phase I
00 11 NSNS
60 months 60 months [46][46]
End of phase IIEnd of phase II
1 (4%)1 (4%) 6 (26%)6 (26%) 0.0320.032
The BHF-funded ‘DMD Heart-Protection Study’The BHF-funded ‘DMD Heart-Protection Study’ - - AimsAims
…………to determine whether starting to determine whether starting
♣♣combination therapycombination therapy with ACE-inhibitor & beta-blockerwith ACE-inhibitor & beta-blocker
♣♣before the onsetbefore the onset of echo-detectable LV dysfunction of echo-detectable LV dysfunction
♣♣delays onset or slows cardiomyopathy progression ratedelays onset or slows cardiomyopathy progression rate
♣♣five-UK-centre, double-blind, randomised, placebo-five-UK-centre, double-blind, randomised, placebo-
controlled trialcontrolled trial
♣♣over 5 yearsover 5 years
The BHF-funded ‘DMD Heart-Protection Study’The BHF-funded ‘DMD Heart-Protection Study’
Inclusion CriteriaInclusion Criteria
Aged 6-10 yearsAged 6-10 years
♣♣LVEF LVEF >> 60% 60% (normal range = 63 (normal range = 63 ++ 5%) 5%)
♣♣No global or regional wall motion abnormalities No global or regional wall motion abnormalities
(echocardiogram)(echocardiogram)
♣♣ Informed consent from children & parents / guardians Informed consent from children & parents / guardians
♣♣No contra-indication to perindopril or bisoprololNo contra-indication to perindopril or bisoprolol
The ‘DMD Heart-Protection Study’: The ‘DMD Heart-Protection Study’: Test Test scheduleschedule
Initial Initial VisitVisit
66
mthsmths
1212 1818 2424 3030 3636 4242 4848 5454 6060
Symptoms / Symptoms / adverse effects adverse effects reviewreview
♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥
EchocardiogramEchocardiogram ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥
12-lead ECG12-lead ECG ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥
Blood sample***Blood sample*** ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥
FEV1 / VCFEV1 / VC ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥
Quality of life Quality of life questionnairesquestionnaires ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥ ♥♥
The BHF funded ‘DMD Heart-Protection Study’The BHF funded ‘DMD Heart-Protection Study’
♣♣ Primary end-pointPrimary end-point
Change in LVEF% compared to baseline, after a minimum of two Change in LVEF% compared to baseline, after a minimum of two years of combination therapy or placeboyears of combination therapy or placebo
♣♣ Secondary end-pointsSecondary end-points
i) Death from any cause i) Death from any cause
ii) Development of symptoms of cardiac failureii) Development of symptoms of cardiac failure
iii) Sufficient objective deterioration in LV function, without iii) Sufficient objective deterioration in LV function, without symptoms, to make continuing placebo therapy symptoms, to make continuing placebo therapy
unethicalunethical
Progressive reduction in LVEF% over at least two Progressive reduction in LVEF% over at least two assessments at assessments at least 3 months apart, resulting in LVEF < 35%least 3 months apart, resulting in LVEF < 35%
The BHF funded ‘DMD Heart-Protection Study’The BHF funded ‘DMD Heart-Protection Study’
Power CalculationPower Calculation
♣♣ The sample size is based on a composition of change The sample size is based on a composition of change in LVEF% over the 5 year term of the in LVEF% over the 5 year term of the study. study.
♣♣ A difference of 5% between treatment groups was A difference of 5% between treatment groups was considered to be the smallest that would represent a considered to be the smallest that would represent a clinically useful gain. clinically useful gain.
♣♣ The standard deviation of LVEF was taken to be 10% The standard deviation of LVEF was taken to be 10% and this gives two groups of 64 subjects to yield a and this gives two groups of 64 subjects to yield a power of 80% at the 5% significance level & allowing power of 80% at the 5% significance level & allowing for 10% withdrawal due to adverse effectsfor 10% withdrawal due to adverse effects
Number of patients required = Number of patients required = 140 - Start early 140 - Start early 20062006
Phase I/II trials in DMDPhase I/II trials in DMD
Antisense oligonucleotidesAntisense oligonucleotides Myostatin inhibitionMyostatin inhibition PCT 124PCT 124 ……………………..
Antisense oligonucleotidesAntisense oligonucleotides Phase 1 clinical trials in the use Phase 1 clinical trials in the use
antisense oligonucleotides are planned antisense oligonucleotides are planned in UK for April 2006in UK for April 2006
Newcastle and London collaborating in Newcastle and London collaborating in the UK consortiumthe UK consortium
European consortium (ENMC/Leiden)European consortium (ENMC/Leiden) Glaxo philanthropic initiative (Steve Glaxo philanthropic initiative (Steve
Wilton Aus)Wilton Aus) Other centres around the world are also Other centres around the world are also
conducting trials using antisense conducting trials using antisense technologytechnology
Concept of Concept of oligonucleotide oligonucleotide
therapy for DMDtherapy for DMD Antisense oligoribonucleotides (AON) used to Antisense oligoribonucleotides (AON) used to
exclude specific exons by interference with exclude specific exons by interference with splice sites or exon recognition sequences.splice sites or exon recognition sequences.
Estimated that 10 AONs would treat 70% of Estimated that 10 AONs would treat 70% of DMD cases (van Deutekom et al., 2001).DMD cases (van Deutekom et al., 2001).
Concept of exon skipping is Concept of exon skipping is simple but there are simple but there are
challenges...challenges... Must identify the mutation to tailor the Must identify the mutation to tailor the
treatmenttreatment
Efficacy of exon skipping is influenced Efficacy of exon skipping is influenced byby Genetic bandaid designGenetic bandaid design
Nature of AO chemistry and modifications Nature of AO chemistry and modifications
Dystrophin expression : 6 weeks after Dystrophin expression : 6 weeks after injection of morpholino AO into TA of 11-day injection of morpholino AO into TA of 11-day
old old mdxmdx mouse mouse
4x 10x inset8% central nuclei
22% central nuclei
Morpholino with enhanced nuclear Morpholino with enhanced nuclear uptake: uptake: 10 days10 days afterafter single ip injection into single ip injection into
mouse @ 10mg/kg mouse @ 10mg/kg (other tissues negative) slides from (other tissues negative) slides from Steve Wilton Steve Wilton
Mdx diaphragm C57Bl 10 diaphragm
Exon skipping and DMDExon skipping and DMD
Exon skipping can not cure DMDExon skipping can not cure DMD
May reduce severity May reduce severity some mutations should respond better than some mutations should respond better than
othersothers more efficient exon skippingmore efficient exon skipping more functional protein being inducedmore functional protein being induced
Not applicable to all dystrophin mutationsNot applicable to all dystrophin mutations large genomic deletions large genomic deletions DDy--------y--------NN loss of crucial binding domains loss of crucial binding domains DDystrophiystrophi
Clinical trialsClinical trials
Must demonstrate safety first Must demonstrate safety first
Intramuscular administration should demonstrate Intramuscular administration should demonstrate proof of principle but is unlikely to be a viable proof of principle but is unlikely to be a viable clinical optionclinical option
AO administration must be achieved systemicallyAO administration must be achieved systemically
Must go with best AOs rather than addressing most Must go with best AOs rather than addressing most common mutation to demonstrate efficacycommon mutation to demonstrate efficacy
cocktail of AOscocktail of AOs multiple exon skipping strongly and consistently inducedmultiple exon skipping strongly and consistently induced would address more mutations than a single compound would address more mutations than a single compound provide additional sequence specific safety and toxicology provide additional sequence specific safety and toxicology
informationinformation
How can we determine the How can we determine the impact of new treatments in impact of new treatments in
DMD?DMD? Clinical assessments previously used have not Clinical assessments previously used have not
been rigorously evaluated for reliability, been rigorously evaluated for reliability, reproducibilityreproducibility
Functional assessments have reflected the ability Functional assessments have reflected the ability of the untreated child and have not previously of the untreated child and have not previously considered potential for improved abilityconsidered potential for improved ability
Biopsies to evaluate changes in muscle are Biopsies to evaluate changes in muscle are unethical especially repeated and unwanted by unethical especially repeated and unwanted by children and parentschildren and parents
We are currently working on new techniques to We are currently working on new techniques to evaluate muscle structure and collaborating in evaluate muscle structure and collaborating in the development of clinical assessmentthe development of clinical assessment
Assessment of muscle fibre Assessment of muscle fibre damage in patients with damage in patients with
Duchenne muscular Duchenne muscular dystrophy by MRIdystrophy by MRI
Penny GaroodPenny Garood
Volker StraubVolker Straub
Michelle EagleMichelle Eagle
Background Background
MRI routinely used to investigate MRI routinely used to investigate muscle pathologymuscle pathology
Late-stage appearance of DMD well Late-stage appearance of DMD well characterised – fatty replacement characterised – fatty replacement and fibrosisand fibrosis
Less research on earlier stages, Less research on earlier stages, progression in distinct muscle groups progression in distinct muscle groups and use of gadolinium contrastand use of gadolinium contrast
AimsAims
To develop and evaluate MRI methods for To develop and evaluate MRI methods for measuring degree and distribution of measuring degree and distribution of muscle damage (response to treatment)muscle damage (response to treatment)
Definition of stages of muscle disease by Definition of stages of muscle disease by MRI in DMDMRI in DMD
3 contrast-enhanced MRI scans over 2 years3 contrast-enhanced MRI scans over 2 years
Detection of exercise-related muscle Detection of exercise-related muscle changes by MRIchanges by MRI
Step test (eccentric exercise) and MRI 4 days laterStep test (eccentric exercise) and MRI 4 days later
Eligible BoysEligible Boys
Boys aged ≥ 6 yearsBoys aged ≥ 6 years Independently ambulant (50m) and Independently ambulant (50m) and
able to complete step testable to complete step test Confirmed diagnosis of DMDConfirmed diagnosis of DMD Possible cooperation with assessmentPossible cooperation with assessment Written informed consent Written informed consent
parent/guardianparent/guardian
Step TestStep Test Eccentric exercise known to cause loss Eccentric exercise known to cause loss
sarcolemmal integrity in normals sarcolemmal integrity in normals rise in CK rise in CK MRI changes (peak day 4)MRI changes (peak day 4)
In DMD, common daily movements causing In DMD, common daily movements causing eccentric contractions may cause focal eccentric contractions may cause focal sarcolemmal disruptionssarcolemmal disruptions
Does eccentric exercise produce changes on Does eccentric exercise produce changes on MRI ?MRI ?
Study started September 05Study started September 05
Clinical AssessmentClinical Assessment With the promise of future therapies comes With the promise of future therapies comes
a need for reliable evaluation of the clinical a need for reliable evaluation of the clinical impact of treatmentimpact of treatment
We are collaborating in a national strategy We are collaborating in a national strategy to standardise clinical evaluation in the UKto standardise clinical evaluation in the UK
North Star projectNorth Star project Aims to Aims to
To optimise and standardise the management To optimise and standardise the management and care of children with neuromuscular and care of children with neuromuscular disease in paediatric centres throughout the disease in paediatric centres throughout the UKUK
Project overviewProject overview Clinical network Clinical network National database DMD children – starting with National database DMD children – starting with
those who are still ambulant and in 5-7 year old those who are still ambulant and in 5-7 year old groupgroup
Data base will include specific detail of mutation Data base will include specific detail of mutation so that when a treatment becomes available so that when a treatment becomes available suitable children can be rapidly identifiedsuitable children can be rapidly identified
Clinical auditClinical audit Standardised assessmentStandardised assessment Equity of treatment across centresEquity of treatment across centres Future links to clinical trialsFuture links to clinical trials
Functional TestingFunctional Testing
North Star Ambulatory AssessmentNorth Star Ambulatory Assessment Timed 10m walk/runTimed 10m walk/run Timed rise from floorTimed rise from floor EK Scale (non-ambulant)EK Scale (non-ambulant)
ActivityActivity 22 11 00
11 StandStand Stands still & symmetrically, Stands still & symmetrically, heels flat, legs neutralheels flat, legs neutral
Stands still, on toes, legs Stands still, on toes, legs abductedabducted
Cannot stand Cannot stand still or indep.still or indep.
22 WalkWalk Heel-toe or flat-footed gait Heel-toe or flat-footed gait patternpattern
Persistent toe walker (cannot Persistent toe walker (cannot walk except upon toes)walk except upon toes)
Loss of indep. Loss of indep. ambulationambulation
33 Sit-standSit-stand Arms folded, start position 90Arms folded, start position 90º º hips & knees with feet on floorhips & knees with feet on floor
Pushes on thighs, on chair or Pushes on thighs, on chair or turns proneturns prone
UnableUnable
44 Stand 1 leg R&LStand 1 leg R&L Can stand in a relaxed manner Can stand in a relaxed manner for count of 3for count of 3
Stands, but momentary, fixation Stands, but momentary, fixation ++
UnableUnable
55 Climb step R&LClimb step R&L Faces ahead, no hand on thigh or Faces ahead, no hand on thigh or railsrails
Goes up sideways or uses Goes up sideways or uses support or hand on thighsupport or hand on thigh
UnableUnable
66 Descend stair Descend stair R&LR&L
Faces stair, climbs down Faces stair, climbs down controlling WB legcontrolling WB leg
Sideways, ‘skips’ down or needs Sideways, ‘skips’ down or needs supportsupport
UnableUnable
77 Rise from floor*Rise from floor* From supine – no Gowers’From supine – no Gowers’ Gowers’ evidentGowers’ evident HAS to use HAS to use furniture/unablfurniture/unablee
88 Get to sittingGet to sitting From supine – may use one hand From supine – may use one hand Self assistanceSelf assistance UnableUnable
99 Lift headLift head In supine – mid-line, chin to chestIn supine – mid-line, chin to chest Lifts head, but thro’ side-F or no Lifts head, but thro’ side-F or no neck flexneck flex
UnableUnable
1010 Stand on heelsStand on heels Both feet, toes off groundBoth feet, toes off ground Hip flexes & only forefoot raisedHip flexes & only forefoot raised UnableUnable
1111 JumpJump 2 feet together, clears ground 2 feet together, clears ground 1 foot after the other (skip)1 foot after the other (skip) UnableUnable
1212 Hop R&LHop R&L Clears forefoot and heel from Clears forefoot and heel from floorfloor
Bends knee and raises heel, no Bends knee and raises heel, no floor clearancefloor clearance
UnableUnable
1313 Run (10m)Run (10m) No double stance phaseNo double stance phase ‘‘Duchenne Jog’Duchenne Jog’ UnableUnable
Gower’s ManoeuvreGower’s Manoeuvre
2 -No evidence of Gowers’ manoeuvre2 -No evidence of Gowers’ manoeuvre 1A - Turns towards the floor and places 1A - Turns towards the floor and places
hand/s on floor to start to rise, does not hand/s on floor to start to rise, does not need to place hands on legsneed to place hands on legs
1B- Turns towards the floor and places 1B- Turns towards the floor and places hand/s on floor to start to rise, one hand hand/s on floor to start to rise, one hand on legon leg
1C - Turns towards the floor and places 1C - Turns towards the floor and places hand/s on floor to start to rise, two hand/s on floor to start to rise, two hands on legshands on legs
0D - 0D - HASHAS to use furniture to use furniture 0E - Unable0E - Unable
Other assessmentsOther assessments
Need to monitor FVC &FEVNeed to monitor FVC &FEV11 absolute and absolute and percentage predicted for heightpercentage predicted for height
MyometryMyometry Manual muscle testingManual muscle testing
Elaine ScottElaine ScottResearch Physiotherapist / North Star Project Research Physiotherapist / North Star Project
CoordinatorCoordinator
emailemail [email protected][email protected] 07795 22717007795 227170
conclusionsconclusions New therapies are on the horizon for DMDNew therapies are on the horizon for DMD We need to be prepared for evaluation of these We need to be prepared for evaluation of these
treatments bytreatments by1.1. Ensuring national and international Ensuring national and international
collaborationcollaboration2.2. Setting up national data bases of patient Setting up national data bases of patient
populationspopulations3.3. Developing and refining clinical assessmentsDeveloping and refining clinical assessments4.4. Preparing therapists for an increasing role in Preparing therapists for an increasing role in
clinical evaluation by high quality training with clinical evaluation by high quality training with international standardsinternational standards
5.5. Finding alternatives to biopsy for evaluation of Finding alternatives to biopsy for evaluation of muscle structure/damage/repair muscle structure/damage/repair
