J.M. Smeets est professeur de clinique génomique à Maastricht, spécialiste des maladies mitochondriales, directeur du centre du génome et d’institutions de recherche.
Son travail porte essentiellement sur le dysfonctionnement mitochondrial dans les maladies métaboliques, cardiovasculaires et neurologiques. L'objectif est d'identifier les causes génétiques, comprendre la pathologie, prévenir la transmission et enfin, développer de nouvelles approches thérapeutiques pour ces troubles souvent fatales.
L’équipe du Pr Smeets a publié en septembre 2015 dans le New York Academy of sciences un article sur « la prévention de la transmission de maladies mitochondriales de l'ADN à l'aide de diagnostic génétique prénatal ou préimplantatoire. ».Il a donné une conférence à l’hôpital Américain au cours des 16 ème jounée dont voici quelques extraits :
Mitochondrial disease :general of local power failure
Threshold of expression mtDNA diseases
Threshold varies among tissues
Mutation percentage can change in time
Relation mutation percentage clinical symptoms often not straightforward
Most pathogenic mutation leading to severe disease are heteroplasmic
Homoplasmic pathogenic mutations exist (LHON mutations), but severe, life-threatening homoplasmic mutations are rare
Prevention the transmission of mitochondrial DNA disease
- Selecting the good guys (healthy oocyte/embryo)
- Oocyte donation
- homo/heteroplasmic mutations
- Prenatal diagnosis
- some heteroplasmic/de novo mutations
- not reliable for most inherited heteroplasmic mutations
- interpretation problematic
- Preimplantation Genetic Diagnosis
- all heteroplasmic mutations
- Kicking out the bad guys (exchange/correct faulty mitochondria)
- Spindle-chromosomal Complex Transfer, Pronuclear Transfer,
Polar Body Genome Transfer -mitochondrial donation
- Genome editing
- Homo/heteroplasmic mutations
- Under development
How far will preimplantation genetic diagnosis in mtDNA disease bring us?
Carriers of all heteroplasmimtDNmutations have a fair chance of having healthy offspring by applying PGD
- PGD is technically safe and reliable (no polar bodies)
- Estimating a “safe” cut-off mutation percentage at which the risk of being affected is acceptably low (risk reduction strategy)
- Based on limited PGD cycles for specific mutations we expect that most mtDNAmutation carriers will have oocytes below this threshold
- Exact cut-off mutation percentage determined by case-by-case counselling
- Selection of male embryos (sex analysis) could definitely eliminate mtDNA disease in future generations (ethical issue)
- Trophectoderm biopsy performed to test m.324A>G in 2 cases, 1 together with Y-chromosome, the other currently debated (most likely technical issue)
How far will nuclear Transfer in mtDNA Disease bring us?
- Spindle, Pronuclear and Polar Body GenomeTransferare capable of generating (almost) mtDNAmutation-free embryos
- The minimal amount of mtDNA carry-over is unlikely to cause disease and is primarily wild-type mtDNA (MMP selection)
- In primates, mice, (abnormally) and fertilized oocytes the methods seem safe, but issues remain (long term effects, epigenetic issues)
- All methods can be used for heteroplasmicand homoplasmic mutations
- The clinical safety of the methods will be tested in the UK by the first clinical trial
- Require sufficient donor oocytes or zygotes (vitrificationpossible)
New approach :genome editing break-down mutated mt DNA
Nucleases can cleave and reduce the mutation load of specific mtDNA mutations in germ cells of mice
Reducing the mutation load prevents transmission to offspring in mice
Technology also works in human oocytes
Promising, but still experimental:
- Reduction mutation load not sufficient for clinical applications
- Safety not yet demonstrated
Towards a future without mitochondrial DNA disease.
- The transmission of mtDNA disease can be effectively stopped by:
- Prenatal Diagnosis: de novomutations, some recurrent mutations
- Preimplantation Genetic Diagnosis: heteroplasmic mutations
- Both methods are safe with a small residual risk based on heteroplasmy level of embryo/foetus
- Future options are nuclear transfer or genome editing technologies:
- Spindle Transfer: homoplasmic and heteroplasmic mutations
- Pronuclear Transfer: homoplasmic and heteroplasmic mutations
- Polar Body Genome Transfer: homoplasmic and heteroplasmic mutations
- Genome Editing: homoplasmic and heteroplasmic mutations
- Residual risk based on carry-over seems low
- Safety of the methods needs to be demonstrated in clinical trial
- Ethical issues need to be settled
- Therapy development is still fundamental as mtDNA disease occurs de novo in1 in 10.000 (not prevented by any of the methods above)
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