Mitochondrial replacement therapy: modifying in-vitro fertilization to combat mitochondrial disease
Mito chrond ri a l re pl a ce m e nt thera py ( M RT ) , of ten refer red to a s “ 3 - pers on inv i tro fertilizat i o n ( I V F ) ,” i s a te c h nol og y t hat com bi nes t he m i toc hond r ial D N A (mtDNA) o f a do no r w i t h the n ucl ea r DN A of a coupl e i n a n em b r yo t hat is carried to term. T hi s te ch no l o gy ha s been p rop os ed to prevent t he t ra ns m i s s ion of maternally tra nsm i tte d m i to cho nd r i a l d i s ea s e. M i toc hondr i a l di s ea s es a re of ten caused by ge neti c m utati o ns affec t i ng bot h a dul t s a nd c hi l d ren, t hat can lead to diseases a cro ss m ul t i p l e o rga n s a n d have no c ure. W hi l e st rateg i es ex ist to prevent the ve rti ca l t ra nsm i ssi o n of m u tated mt DN A , s u c h a s a dopt i on , or eg g and e mbr yo do nat i o n, t he l a ck o f a ge neti c l i nk does pos e a probl em for s om e couples l ooking to have chi l dre n . I n t hi s a r t i c l e, we w i l l di s c us s t he h i stor y behi n d MRT, its s uccesses and so m e et hi ca l co nce r n s a n d cont rovers i es t h at have a r i s en s inc e its i nc ept i on.
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he research that went into the modern processes of MRT began as early as the 1980s when Dr. Jacques Cohen and others used cytoplasmic transfer to assist in reproduction. Cytoplasmic transfer is a process in which a small amount of cytoplasm from a healthy donor’s oocyte is transferred to an oocyte from a person experiencing fertility issues. The first baby was born from this technique in 1997. Prior to regulation of this technique by the USA’s Food and Drug Administration in 2002, Cohen’s clinic used this technique for the conception and birth of 13 children. Since then, the promising research has led to the birth of 30-50 children worldwide (as of 2016). In 2009, two research teams published studies on mitochondrial donation that progressed the technology further. In 2010, Craven et al. conducted human trials with oocytes that yielded a carryover rate of only 2% mutated mtDNA. In 2015, the UK passed the Human Fertilization and Embryology (Mitochondrial Donation) Regulations making mtDNA donation legal under rare cases where a couple is at a higher risk of transmitting mitochondrial disease to their children. Since then, this technique has seen to the births of several children, including fewer than five children in the UK as of April 2023. While this procedure has been used and/ or approved in some countries (Greece, Ukraine, Australia, Mexico), it is still restricted in many countries including Canada and the USA.
In all these techniques, donor refers to a person with healthy mitochondria, and recipient refers to a person with mutated mtDNA that is trying to conceive a child. In spindle transfer, the spindle-chromosome complex that contains the genetic material from the recipient is removed from an egg during cell division. This spindle-chromosome complex is inserted into a donor oocyte with the nucleus removed. This egg is fertilized and investigated for genetic mutations, particularly in the mtDNA, prior to implantation in the recipient. In pronuclear transfer, an oocyte is removed from the recipient and donor. Both oocytes are fertilized with sperm from the same person. All pronuclei (nucleus from sperm or egg cells) are removed from each fertilized egg prior to the fusing, and the pronuclei from the recipient is transferred into the fertilized egg from the donor. Like in the spindle transfer procedure, the egg is investigated for genetic mutations prior to implantation.
The final technique is the newest and is called polar body transfer. A polar body is a small cell with very little cytoplasm that is created when an egg cell divides. In polar body transfer, a polar body from the recipient is used in its entirety instead of nuclear material from the recipient’s egg as in the other methods. This is a promising technique as polar bodies have very Methods of MRT few mitochondria, thereby reducing the risk of transmitting The historical method of cytoplasmic transfer is no longer recipient mitochondria compared to maternal spindle transfer used in modern procedures of MRT. Rather three main methand pronuclear transfer which have small carryover of recipods exist: maternal spindle transfer, pronuclear transfer, and ient mitochondria. Despite this, polar body transfer requires more recently, polar body transfer. further research to increase reproducibility and replication. 14 IMMpress Vol. 11 No. 2 2023
