US regulator considers science of mitochondrial replacement

24 February 2014

US regulator the Food and Drug Administration (FDA) has released a new briefing on scientific and clinical issues relating to oocyte modification, ahead of a meeting on the topic to be held on 25-26th February.

The topic under consideration is the controversial technique of mitochondrial replacement, also called cytoplasmic transfer, an ingenious method to allow women with inherited forms of mitochondrial disease to have biological children without diseased mitochondria by using a healthy donor egg combined with the nuclear genetic material of the prospective mother for IVF. It can also be used to help women who are infertile due to defective mitochondria conceive biological children.
 
Offspring born following such manipulations have mitochondrial DNA from the anonymous female donor; this accounts for only a very small proportion of the total DNA, all the rest of which is derived from the parents. However, this process creates a permanent (germline) change to the genetic makeup of that individual, which will be passed on to any children they go on to have, which has hitherto not been permitted in any jurisdiction.
 
The UK is pushing ahead for use of the technique, with new regulations to permit its use in production (although safety concerns and ethical and legal objections have previously been raised) and the US is also considering the issue. The Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) will discuss it on 25-26th February 2014. The meeting will include opportunities for expert and public submissions to the panel for consideration, and a briefing document has been released in advance.
 
This outlines evidence behind the key issues under consideration, which are scientific, technologic, and clinical issues relevant to potential future clinical trials of the technique; whilst the existence of ‘ethical and social policy issues’ relevant to regulatory issues are also noted, they are not the subject of this particular meeting. Rather, the document sets out the biology of mitochondria, the basis of mitochondrial disease and infertility arising from mitochondrial dysfunction; new techniques relating to these issues; and specific safety concerns, clinical trial considerations and questions for discussion.
 
Potential risks to women receiving IVF after mitochondrial manipulation are noted:
  • failure to become pregnant
  • failure to deliver a child
  • risks associated with the mitochondrial manipulation procedure
  • toxicities of the reagents used in mitochondrial manipulation
Potential risks children born via the technique are said to be:
  • mitochondrial disease due to  carryover of abnormal mitochondria and heteroplasmy disease caused by nuclear-mitochondrial incompatibility
  • disease caused by epigenetic modifications
  • birth defects associated with the specific mitochondrial manipulation procedure
  • toxicities of reagents used in mitochondrial manipulation
Of note, there are also safety concerns for subsequent generations arising from harmful epigenetic changes and also from the potential for the magnification of small amounts of mutated mitochondrial DNA in the female germline, posing a potential risk of mitochondrial disease in the children of girls born following mitochondrial manipulation.