Mitochondrial Diseases Patient Engagement Day London · Elamipretide / Bendavia. An Observational...
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Mitochondrial Diseases Patient Engagement Day
London
Dr Robert Pitceathly
Saturday 13th October 2018
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Overview
• Mitochondria and mitochondrial diseases
• Mitochondrial disease genetics: mitochondrial DNA and nuclear DNA
• Current treatment strategies
• Research studies and clinical trials
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Mitochondria and mitochondrial diseases
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The mitochondrion
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mtDNA and mitochondrial diseases
>250 pathogenic mutations
0
16,569
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Maternal Inheritance of mtDNA
Colours reflect inheritance of the same mitochondrial genome
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Nucleus containingChromosomes
(99.9% of genetic Information - hair colour
blood group etc)
mtDNA disease
Mitochondria(batteries)
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Nuclear DNA mitochondrial disease
37 genes > 1,500 genes
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Genes of mitochondria-localised proteins linked to human disease
Koopman WJ et al. N Engl J Med 2012;366:1132-1141
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Nuclear DNA mitochondrial disease
Recessivee.g. some formsof Leigh Disease
unaffected Unaffected carrierdisease
Each child has 1 in 4 chance of disease
Dominant Each child has 1 in 2 chance of disease
A/B A/B
A/B A/BB/B A/A
A/B
A/B A/B
B/B
B/BB/B
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Mitochondrial DNA mitochondrial disease
Not ‘Yes’ or ‘No’?Nuclear:
e.g. Dominantinheritance
well
welldisease
disease
But how much?
22%94%
56%
Mitochondrial:Maternal
inheritance
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So things are complicated...
Nuclear DNA disease MtDNA disease
Dominant
Inheritance: Inheritance:
MaternalRecessive
X-linked
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Less mitochondria – less energy
Nucleus containingChromosomes
(blueprint)Mitochondria
(batteries)
Human Cell(the machine)
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7/44 0/4 1/11 3/14 2/16
13 polypeptide subunits
mtDNA
nDNA
Genetic variability
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Clinical variability
Diabetes
Myopathy
Peripheral
Neuropathy
Deafness
CVA / Seizures /
Developmental Delay
Respiratory Failure
Cardiomyopathy /
Conduction Defects
Short stature /
Marrow Failure
Liver /
Renal
Failure
Optic Atrophy / Retinitis
Pigmentosa / Cataracts
Hypothyroidism
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Clinical variability
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Age of onset
Neonate Infant Child Adolescent Adult Elderly
Congenital
Lactic
AcidosisLS
PMPS
HCM
Alpers KSS
MELAS CPEO
MERRF
NARP
Exercise intolerance
Myopathy
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Any age
Any course
Any organ
Any mode of inheritance
G. Mendel Maternal Inheritance
Mitochondrial disorders: unravelling the complexity
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From clinical assessment to genetic diagnosis
Age, Phenotype, Pedigree
Common mtDNA point mutations
(3243, 8344, 8993)
RFLP >1%
MUSCLE
Large scale
rearrangements
- LPCR, SB >5%
Nuclear maintenance
panel (21 genes)
Targeted exome
(300 mito genes)
Full mtDNA
Sequencing
- NGS >10%
(>1% known mutation)
BLOODURINE >20 years
BLOOD < 20 Years
Full mtDNA
Sequencing
- NGS
MUSCLE
Large scale
rearrangements
- LPCR, SB
mtDNA copy
number
- RT-PCR
BLOOD
Exome/Genome
(Research)
-ve -ve
-ve-ve
I
II
III
IV
Histopathology
(COX/SDH, RRF)
Biochemistry
(RCEA, BN-PAGE)
-ve-ve
Functional studies
Modelling
Additional families
Novel mutations/genes
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Current treatment strategies
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Drugs
Stem cells
New proteins
Peptide nucleic acid tRNA enzymes
mtDNA
Gene transfer Targeted nucleases
Exciting times!
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What about now!
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Pharmacological agents, vitamins and related substances
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CoQ10
-lipoic acid
Vitamin C/E
Folate/Folinic acid
L-Arginine/Citrulline
Succinate Idebenone
Creatine
Thiamine
Riboflavin
Carnitine
Vitamins, cofactors and food supplements
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Pharmacological agents and vitamins
Treatment for mitochondrial disorders (2012)• >1300 abstracts (1966-2012)
• 12 RCTs: – Coenzyme Q10
– Creatine
– Creatine/Q10/lipoic acid combo
– Dichloroacetate
– Dimethylglycine
– Cysteine
• No evidence supporting use of any intervention in mitochondrial disorders
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Kanabus. Br J Pharmacol. 2014 Apr; 171(8): 1798–1817.
Randomised, double-blinded, placebo-controlled clinical trials in mitochondrial disease
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Kanabus. Br J Pharmacol. 2014 Apr; 171(8): 1798–1817.
Randomised, double-blinded, placebo-controlled clinical trials in mitochondrial disease
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Kanabus. Br J Pharmacol. 2014 Apr; 171(8): 1798–1817.
Randomised, placebo-controlled, double-blind, clinical trials in mitochondrial disease
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Biochim Biophys Acta. 2015 Jun-Jul;1847(6-7):544-57
Reactive oxygen species and their detoxification
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Mitochondrial diseases with specific treatment options
Brain. 2017 Feb;140(Pt 2):e11.
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Mitochondrial diseases with specific treatment options
Brain. 2017 Feb;140(Pt 2):e11.
Mitochondrial
diseases with
spontaneous
recovery
“Benign” reversible
mitochondrial
myopathy
Acute liver failure
in infancy (TRMU)
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Exercise and diet
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Exercise• Important for general fitness : exercises muscles and keeps heart and
circulation healthy
• If you become unfit can adversely affect muscles
• In many patients’ muscles there is a mixture of good and badmitochondria; the hope is that exercise can increase the goodmitochondria, boosting the level of ATP so avoiding symptoms
• This remains a theory and there are large trials looking at this idea
• Current advice is to exercise regularly at a level that is comfortable,but without pushing yourself to the point that the muscles becomepainful
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Dietary modification• Ketogenic (high fat / low carbohydrate) diet:
promotes formation of ketone bodies (via FAO)
• Ketone bodies:
– Alternative energy source for brain, heart and muscle
– Associated with OXPHOS gene expression (akin to starvation)
– Possibly stimulate mitochondrial biogenesis
• No randomized, double-blinded trial data
• PDH deficiency
• Seizures
• Dietetic supervision!
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Health surveillance and monitoring
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Clinical variability
Diabetes
FatigueMyopathy
Exercise intolerance
Peripheral neuropathy
Deafness
Stroke / Seizures Developmental DelayMovement Disorders
Respiratory Failure
Cardiomyopathy Conduction Defects
Short statureMarrow Failure
Liver / Renal FailureDysphagiaGut dysmotility
Hypothyroidism
PtosisOptic AtrophyRetinitis PigmentosaCataracts
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Surveillance = early treatment
DietDrugsInsulinEnzymes
CoQ10/exercisePT/OT/exercise
Energy conservation
Foot careOrthoticsSurgery
Hearing aidsCochlear implants
AEDsBotox and drugsTendon release DBS
VentilatorsupportDrugs
PPMICDAblationTransplant
Growth hormoneTransfusionTransplant
Dietician SALTPEGLaxativesMicrobiomeDialysisTransplant
PhotocoagulationPtosis surgeryEyelid propsCataract surgeryPrisms
ThyroxineRadioiodineSurgery
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Guidelines - http://mitochondrialdisease.nhs.uk
For patients and professionals…
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Emergency plans and acute management
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Emergency plan
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Acute management
• Early recognition of warning signs:
– Nausea and vomiting
– Confusion, sleepiness or irritability
– Weakness, numbness or speech problems
– Visual or hearing disturbance
– Seizures
– Severe headaches
– Sudden bowel problems
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Acute management
• Seek medical attention early (GP or A&E)
• Ensure any infection treated and well hydrated
• Review medications
• Admit to hospital for:
– Intravenous fluids
– Intravenous antibiotics
– Correction of acidosis
– Wide bore NGT, enemas, fluids +/- TPN for IPO
– Stroke-like episodes = seizure control
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QS Mitochondrial Disease Research studies
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Lower urinary tract symptoms and sexual dysfunction in
mitochondrial disease – completed
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Mitochondrial disease can affect bowel function
Background
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Mitochondrial disease can affect bowel function
We asked:Can mitochondrial disease cause lower urinary tract symptoms (LUTS) and sexual dysfunction too?
?
Background
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• Questionnaire study
• Comparing
• 58 people with genetically
confirmed mitochondrial disease
• 19 unaffected individuals
Methods
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* *
*
• Adults with genetically confirmed
mitochondrial disease frequently
experience LUTS (84%)
• Overactive bladder symptoms
(urinary urgency, the sudden
compelling urge to urinate) most
common 82%
• Overactive bladder symptoms and
low stream symptoms (weak urine
stream, difficulty starting urination)
are more common in patients than
in unaffected individuals (*)
Results: LUTS
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0
10
20
30
40
50
60
70
80
Pe
rcen
tage
wit
h s
exu
al d
ysfu
nct
ion
Sexual dysfunction
*
*
• Sexual dysfunction is more
common in females with
mitochondrial disease than
unaffected females
• Sexual dysfunction is very common
in those with m.3243A>G mutation
(66.7%)
Results: Sexual Dysfunction
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• LUTS are common in individuals with mitochondrial disease
• Despite several effective treatments available for LUTS, most
were untreated
• Sexual dysfunction is common in female mitos and those with
m.3243A>G
• This work will help ensure physicians and patients are aware
of LUTS and sexual dysfunction symptoms in mitochondrial
disease, so they are identified and treated, improving quality
of life
Conclusions
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Vestibular dysfunction: a frequent problem in adult mitochondrial disease
– completed
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MethodGenetic diagnosis of mitochondrial
disease (n=36)
Clinicopathological diagnosis of
mitochondrial disease (n=4)
Patients with suspected
balance disorder seen in
specialist mitochondrial clinic
(n=40)
Referred to specialist
neuromuscular physiotherapist
to complete vestibular and
neurological assessment
(n=40)
Non-vestibular causes of
dizziness and imbalance (n=7)
Cerebellar
syndrome (n=5)
Biomechanical
falls (n=2)
Referred to Neuro-Otology for
full audiovestibular
assessment (n=33)
Genetic diagnosis of mitochondrial
disease (n=29)
Clinicopathological diagnosis of
mitochondrial disease (n=4)
JNNP in press
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Results• Suspected balance disorder: 91% (30/33)
• Minimum prevalence of vestibular abnormality: 26% (30/114)
Yes
No
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• Peripheral vestibulopathy: 77% (23/30)
Yes
No
Results
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Importance – treatment available!
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Mood in mitochondrial disease– ongoing
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Mood and quality of life in mitochondrial diseases
We started evaluating carefully the presence of subtle mood alterations in
mitochondrial diseases
Mood
alterations
Mitochondrial dysfunction
Clinical
Symptoms
WHY: early identification of mood alterations may lead to appropriate
management
HOW: set of questionnaires exploring different aspects of mood involvement
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To better understand the role of mitochondria on
mood alterations
Mood and quality of life in mitochondrial diseases
Pilot study
• Evaluate which questionnaires are the most appropriate for evaluating mood
• Evaluate the frequency of mood alterations and how they relate to clinical symptoms
To improve clinical management of
mitochondrial diseases
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QS Mitochondrial DiseaseClinical Trials
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Elamipretide / Bendavia- UCL and Newcastle (UK)
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Elamipretide / Bendavia
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An Observational Study of Patients With Primary Mitochondrial Disease (SPIMM-300)
Inclusion Criteria
• Genetic diagnosis of mitochondrial disease
• Patient can provide informed consent
• Patient 16 and 65 years of age
• Signs or symptoms of mitochondrial myopathy (fatigueability, exercise intolerance, muscle pain)
• Ambulatory and can walk for 6 minutes
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An Observational Study of Patients With Primary Mitochondrial Disease (SPIMM-300)
Patient visits and procedures
• 2 questionnaires: fatigue (8Qu) and PMD symptom assessment (9Qu)
• 6MWT
• 3TUG
• 5XSST
• 6 month follow up telephone call
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SPIMM-301: Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial
to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in
Subjects with Primary Mitochondrial Myopathy Followed by an Open-Label
Treatment Extension
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PART 1 Objectives/Endpoints
Primary Objective
• To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks on the:– Distance Walked (meters) on the 6MWT
– Total Fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA)
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PART 1 Objectives/Endpoints
Secondary Objectives:
• To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks as measured by changes in the:– Fatigue During Activities score on the PMMSA
– Neuro-QoL Fatigue score
– Most bothersome symptom score on the PMMSA
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PART 1 Objectives/Endpoints
Secondary Objectives:
• To evaluate the safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks:– Adverse Events (AEs)/Adverse Device Effects (ADEs)
– Vital Signs
– Electrocardiograms (ECGs)
– Clinical laboratory evaluations
– Columbia-Suicide Severity Rating Scale (C-SSRS)
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SPIMM-301 PART 1
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PART 2 Objectives/Endpoints
Primary Objective
• To assess the long-term safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for up to 144 weeks.– Adverse Events (AEs)/Adverse Device Effects (ADEs)
– Vital Signs
– Electrocardiograms (ECGs)
– Clinical laboratory evaluations
– Columbia-Suicide Severity Rating Scale (C-SSRS)
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SPIMM-301 PART 2
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PART 2 Continuation Criteria
A subject must meet all of the following PART 2 Continuation Criteria at the Week 24 Visit in SPIMM-301 to be eligible for PART 2:
1. Subjects must continue to be able and willing to adhere to the trial requirements.
2. Subject is appropriate to continue in PART 2 (i.e. subject was compliant in SPIMM-301), in the opinion of the Investigator.
3. Subject has not had a serious adverse event (SAE)/serious adverse device effect (SADE) attributed to the elamipretide delivery system.
4. Subject has not permanently discontinued the elamipretide delivery system.
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Nicotinamide Riboside- Cambridge and UCL
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Less mitochondria = less energy
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More mitochondria = more energy
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The role of Nicotinamide Riboside in Mitochondrial Biogenesis
What’s the study about?Aim of this study is to investigate if Nicotinamide Riboside, a modified B vitamin, can increase energy production and reduce symptoms in humans with mitochondrial disease.
Who’s running the study?Professor Patrick Chinnery and his research team in Cambridge
What’s involved?6 visits to Addenbrooke’s Hospital, Cambridge:
❑ Visit 1: MRI scan, muscle biopsy, 6 minute walk test, timed up and go, grip strength, questionnaires.
❑ 4 weeks of Nicotinamide Riboside supplementation❑ Visits 2-5: blood samples and progress check.❑ Visit 6: MRI scan, muscle biopsy, 6 minute walk test, timed up and go, grip
strength, questionnaires.
Who’s eligible?Men and women aged 18-70 years, with a confirmed diagnosis of:
❑ Mitochondrial disease caused by the m.3243A>G mutation in mitochondrial DNA❑ Progressive external ophthalmoplegia (PEO) plus exercise intolerance/fatigue,
caused by a single deletion of mitochondrial DNA
Zoe McIntyre01223 331506
[email protected]@mrc-
mbu.cam.ac.uk@cam_mito
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2-Deoxyglucose- UCL
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Less healthy mitochondria = less energy
Nucleus containingChromosomes
(blueprint)Mitochondria
(batteries)
Human Cell(the machine)
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More healthy mitochondria = more energy
Nucleus containingChromosomes
(blueprint)Mitochondria
(batteries)
Human Cell(the machine)
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2-Deoxyglucose experimental medicine study
• Modified sugar molecule
• Reduces mutant 3243G in patient skin cells
• Has been used in humans in cancer and epilepsy
Study design
• Stage I (4 patients) → 8 weeks escalating dose
• Stage II (6 patients) → 12 week study to measure whether 2DG reduces 3243G levels in humans (will involve muscle biopsies pre- and post-treatment)
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Summary• Diagnosing mitochondrial disease can be challenging;
multidisciplinary approach crucial
• No evidence from trials for current treatments apartfrom specific scenarios – but lots we can still do
• Surveillance and treatment of complications andrecognising warning signs early essential
• Lots of active research studies and preclinical and earlyphase clinical trials ongoing
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Acknowledgments
▪ Prof M Hanna
▪ Prof H Houlden
▪ Prof M Reilly
▪ Dr R Quinlivan
▪ Dr C Turner
▪ Dr M Parton
▪ Dr O Poole
▪ Dr E Bugiardini
▪ Ms S Holmes
▪ Ms N James
▪ Ms M Skorupinska
▪ Ms I Skorupinska
▪ Ms L Germain
▪ Mr D Kozyra
▪ Dr J Holton
▪ Dr R Phadke
▪ Dr J Polke
▪ Ms C Woodward
▪ Dr R Labrum
▪ Prof S Heales
▪ Dr A Lam
▪ Dr I Hargreaves
▪ Dr A Chalasani
▪ Dr M Madej
▪ Dr A Male
▪ Dr D Kaski
▪ Dr G Ramdharry
▪ Prof D Turnbull
▪ Prof R Taylor
▪ Dr R McFarland
▪ Dr A Schaefer
▪ Dr G Gorman
▪ Dr Yi Ng
▪ Prof J Poulton
▪ Dr V Nesbitt
▪ Dr C Fratter
▪ Dr C Smith
▪ Dr G Brown
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Lots of exciting research and trials inmitochondrial disease – speak to Louise, Iwonaor Mariola to register your interest!
[email protected]@nhs.net [email protected]