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![Page 1: Therapeutic avenues Louise Hyslop. 1. Reproductive technologies to prevent transmission of mitochondrial DNA disease 2. Clinical trials and potential.](https://reader036.fdocuments.us/reader036/viewer/2022062722/56649f395503460f94c56878/html5/thumbnails/1.jpg)
Therapeutic avenues
Louise Hyslop
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1. Reproductive technologies to prevent transmission of mitochondrial DNA
disease
2. Clinical trials and potential therapies for nuclear mitochondrial diseases
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• Mitochondria contain own DNA (mtDNA)
• Multiple copies of mtDNA in each cell
• mtDNA can have mutations
• Mitochondria contain own DNA (mtDNA)
• Multiple copies of mtDNA in each cell
• mtDNA can have mutations
MitochondriaMitochondria
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MtD
NA
co
py
nu
mb
er
(n=19)
mtDNA: inherited only from our mothersmtDNA: inherited only from our mothers
Human eggs contain abundant stock of mtDNA
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Mutations can be present in all, or just some copies of mtDNA
Severity of disease is determined by the ratio of mutated to non-mutated mitochondrial DNA
mtDNA mutationsmtDNA mutations
100% mutation
0% mutation
mix of mutated and normal mtDNA
Homoplasmy Heteroplasmy
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MutationLoad
Mother
Reproductive consequencesReproductive consequences
Son78%
Died aged 7 years
Mild clinical
symptoms
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MutationLoad
Mother 38%
Reproductive consequencesReproductive consequences
Daughter 0%
Son78%
Died aged 7 years
Mild clinical
symptoms
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Mutation load
Mutation load
Wide variation in mtDNA mutation loads between eggs and embryosWide variation in mtDNA mutation loads between eggs and embryos
0% 78%
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Summary of cases at Newcastle Fertility CentreSummary of cases at Newcastle Fertility Centre
xx xx Case C
xx xx
x Case D
x
Case B
xxxx
Case A
xxxxx
x20
40
60
80
100
xx
Case E
% m
utat
ion
load
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What can we offer in cases where all embryos have a high mutation load?What can we offer in cases where all embryos have a high mutation load?
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Mutation loadMutation load
Can we uncouple the inheritance of
nuclear and mtDNA?
Can we uncouple the inheritance of
nuclear and mtDNA?
Transplantation of the nuclear DNA
Transplantation of the nuclear DNA
mutant mitochondriawild-type mitochondria
Are there alternative strategies?Are there alternative strategies?
Not feasible to replace the
mitochondria
Not feasible to replace the
mitochondria
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• Proven to be compatible with development in mice (McGrath and Solter, 1983; Meirelles & Smith, 1997)
• Proven to prevent transmission of a mitochondrial DNA deletion in mice (Sato et al, PNAS, 2005)
Pronuclear transferPronuclear transfer
Fertilised egg
Pronuclei
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Donor egg
Egg from affected woman
mutant mitochondriawild-type mitochondria
Pronuclear transfer strategyPronuclear transfer strategy
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• Is it technically feasible in human fertilised eggs?
• Can reconstituted fertilised eggs develop?
• Can we minimise the level of mtDNA carryover?
• Is it technically feasible in human fertilised eggs?
• Can reconstituted fertilised eggs develop?
• Can we minimise the level of mtDNA carryover?
In the lab: Pronuclear transferIn the lab: Pronuclear transfer
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Craven et al, 2010, Nature, vol. 465
Embryo development:(abnormally fertilised eggs)
•Unmanipulated controls: 17%•Pronuclear transfer: 8%
Monitor embryo developmentMonitor embryo development
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Optimisation of the procedure to minimise
carry over of mtDNA
Optimisation of the procedure to minimise
carry over of mtDNA
BeforeBefore
<2%<2%Craven et al, 2010, Nature, 465
8.1± 7.6%8.1± 7.6%mtDNA carry-overmtDNA carry-over
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Donor egg
Egg from affected woman
mutant mitochondriawild-type mitochondria
Conclusion: Pronuclear transfer is a feasible option for reducing the risk of
transmission of mutated mtDNA
Conclusion: Pronuclear transfer is a feasible option for reducing the risk of
transmission of mutated mtDNA
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Effects of pronuclear transfer on embryo development
– Can reconstituted embryos develop with high efficiency?
– Are these reconstituted embryos normal?• Are the manipulations harmful to embryos?
Ongoing work: Testing Safety and EfficacyOngoing work: Testing Safety and Efficacy
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Public consultation
Debate and votes in Houses of Parliament on regulations
Detailed regulations agreed and adopted – Oct 2015
Examination of the safety and efficacy data
Application for licence to use new technique in clinical treatment
Legal and regulatory landscapeLegal and regulatory landscape
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Mitochondrial GeneticsDoug TurnbullLyndsey CravenHelen Tuppen
Egg Donation ProgrammeAlison MurdochMeena ChoudharyMaria NesbittKayleigh Lennox
Reproductive Biology Mary HerbertLouise HyslopLaura Irving Jessica RichardsonDimitri Kalleas
LegalJames Lawford Davies
PGD ProgrammeRob TaylorBobby McFarlaneJane StewartCharlotte AlstonSam Byerley
AcknowledgementsAcknowledgements
Egg donors and patients