Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation

Abstract

Pathogenic mutations in mtDNAs have been shown to be responsible for expression of respiration defects and resultant expression of mitochondrial diseases. This study directly addressed the issue of gene therapy of mitochondrial diseases by using nuclear transplantation of zygotes of transmitochondria mice (mito-mice). Mitomice expressed respiration defects and mitochondrial diseases due to accumulation of mtDNA carrying a large-scale deletion (⌬mtDNA). Second polar bodies were used as biopsy samples for diagnosis of mtDNA genotypes of mito-mouse zygotes. Nuclear transplantation was carried out from mito-mouse zygotes to enucleated normal zygotes and was shown to rescue all of the F 0 progeny from expression of respiration defects throughout their lives. This procedure should be applicable to patients with mitochondrial diseases for preventing their children from developing the diseases. mitochondrial disease ͉ mitochondrial DNA

Mitochondria-related male infertility

“…mito-mice from tail samples (see Table 1, which is published as supporting information on the PNAS web site) without having to kill the mice because the proportions are approximately uniform throughout the tissues of individual mito-mice (9,11,17). Based on the deduced proportions of ⌬mtDNA, we classified the mito-mice into three groups ( Fig.…”

“…Proportions of wild-type and ⌬mtDNA in tissues and sperm collected from mito-mice were determined by real-time detection PCR as described in ref. 17.…”

“…Male mito-mice (4.5-6.5 months old) carrying various proportions of ⌬mtDNA were used for the study. The proportion of ⌬mtDNA in mito-mice was deduced from tail DNA samples because the proportions are very similar in all of the tissues of an individual mouse (9,11,17). Age-matched male B6 mice were also used as normal controls.…”

Prévenir la transmission des mutations de l’ADN mitochondrial : mythe ou réalité ?

“…Cette approche avait été préalablement testée dans des modèles murins porteurs d'un polymorphisme de l'ADNmt [9,10], puis validée chez la souris mitomice portant une délétion de l'ADNmt [11], puisque les souriceaux nés de cette technique étaient indemnes de tout signe clinique et portaient un taux d'hétéroplasmie de l'ordre de 11 %. La stratégie consiste à prélever un caryoplaste contenant les pronucléus mâle et femelle du zygote donneur, à le transférer dans la zone pellucide d'un zygote rece- …”

Progress and prospects: gene therapy for mitochondrial DNA disease

“…Following reconstruction of such a murine embryo, fused zygotes were transferred to the oviducts of pseudopregnant females and offspring were shown to be normal. 21 Could such an approach be possible in humans? Following the decision in 2005 by the UK Human Fertilisation and Embryology Authority to approve research into the feasibility of this approach in humans, experiments have been initiated using abnormally fertilised embryos.…”