What are the safety and ethical implications of mitochondrial transfer?

March 1, 2014Carole No Comments »

In my last post, I wrote about the basics of mitochondrial transfer, how it works, what is new and what is almost two decades old. In a nutshell, it is a method used within the context of IVF to swap out mutated mitochondrial DNA with healthy DNA from a donor either just before or after fertilization occurs. Mitochondrial DNA is different from chromosomal DNA- mitochondrial DNA does not code for traits that are passed from generation from generation. Mitochondrial DNA has a different function; it encodes proteins that are responsible for the basic energy synthesis of ATP which makes our cells “go”. No ATP, the cell is dead. Mutations in mitochondrial DNA cause serious diseases because they cause the mitochondria to malfunction and the ATP powerhouse to malfunction. Eventually, it will kill you or make you very, very sick. So being able to correct this issue in an egg and spare a future child from this dread disease certainly is attractive. But it raises serious ethical and safety issue.

We need to collect much more data in the non-human primates before we introduce this into clinical practice.  Some studies have been done in non-human primates and apparently healthy babies were born. Similar studies have been done using human material but the embryos produced were made into embryonic stem lines to study them, rather than transferred in a clinical procedure.

Both the FDA in the US and the Human Fertilization and Embryo Authority in the United Kingdom are reviewing these new procedures.  In the US, the American Society for Reproductive Medicine sent a message to its members describing efforts to work with the FDA to review these procedures. Follow the links for FDA and HFEA above for more information on the reviews planned.

ASRM BULLETIN (Volume 16, Number 13, February 26, 2014)

FDA Committee Meets to Discuss Oocyte Modification
FDA’s Cellular, Tissues and Gene Therapies Advisory Committee met yesterday and is continuing today to discuss oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility.
Several ASRM members were invited to the committee as special members for this meeting and others are giving presentations.  Prior to the meeting, ASRM submitted the following comment:
To:  Cellular, Tissues and Gene Therapies Advisory Committee
From:  American Society for Reproductive Medicine
The American Society for Reproductive Medicine (ASRM) is a multi-disciplinary organization whose members are physicians, scientists and other health care professionals involved in the field of reproductive medicine.  We appreciate the opportunity to provide comments to the Committee regarding oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility.  ASRM has always recognized that research and clinical practice involving human reproduction and infertility must take into account the unique nature of the tissues, cells and organisms involved in the creation of new life.  We believe the science behind oocyte manipulation to transfer mitochondria is interesting and has promise in treating infertility and preventing the transmission of mitochondrial disease, which are both important goals.  We believe further research in this area is important, and could have clinical applications.  We encourage and support FDA’s efforts to determine how to proceed with evaluating its safety and efficacy, and we would be happy to consult with FDA in pursuing this.

Some of the safety issues identified with the technical process include:

  • Minimizing the amount of mutated mitochondrial DNA that might be carried over from the patient’s egg. It is not clear how much mutated mitochondrial DNA is sufficient to cause disease symptoms.
  • Concern that the fertilization process will go awry if the mitochondrial transfer occurs pre-fertilization using the newly reconstituted egg containing both donor mitochondria and patient chromosomal DNA. Some human embryo studies have shown that the incidence of aneuploidy – a sign of abnormal fertilization– is higher in these “reconstituted eggs”.
  • Both of the mitochondrial transfer techniques require the use of agents, cytoskeletal inhibitor and the hemagglutinating virus of Japan in order to contain and move the maternal DNA on a structure called the egg spindle from the original egg to the empty donor egg with the healthy mitochondria. The safety of these agents in humans has not been fully tested.
  • Concern that in some cases there may be incompatibility between the donor mitochondrial DNA and the patient’s chromosomal DNA, and that the foreign mitochondria can effect gene expression of the zygote’s nuclear genes and cause health problems. Although the mitochondrial DNA does not encode for traits, it can effect the epigenetic expression of the chromosomal genes, meaning it can turn them on or off.
  • Once clinical introduction begins and human children are born from these procedures, it will take decades of health monitoring to provide reassurance that there are no long-term health implications.

Even if we studied non-human primates for decades, there will still be a leaping off point, where we try it in a clinical setting and take some risks with that first human life.  IVF has a long history of introducing clinical techniques after the briefest of animal trials and little or no human experimentation outside the clinic. The reason for this is multi-fold. First,  patients want cures now, not in a decade or two, and there are always doctors who are ready take that leap of faith with them.  Second, NIH does not fund research using embryos so there is little actual research going on to see if IVF techniques are safe. A couple of states are independently funding embryonic stem cell research which could be used to study these mitochondrial transfer techniques but there is no large federal budget for this. This lack of federal funding arose out of the abortion debate.  In the US, we have decide that we won’t support federal research to test whether new IVF procedures are safe but it is fine for patients to pay for an experiment in the guise of a clinical procedure because that is freedom, I guess. Freedom to be a guinea pig.

I am conflicted about these new techniques and how best to find the balance between risks vs. benefits of new interventions. Mitochondrial diseases are truly horrible. I attended the funeral of a colleague’s child. At birth until about 2 years of age, this child, a boy, appeared perfectly healthy, then he slowly lost every function he had acquired in those two years. It was like aging backward, talking in sentences to words then to sounds, walking to crawling, to sitting, to laying, to being a vegetable for years until his death relieved him of a life-less life at about 8. His brain was gone long before the basic functions of his brain stem gave up, ground to death by a faulty energy system. He inherited this mutation in his mitochondria from his mother. This couple also had two normal children together.

How else can the misery of inherited mitochondrial mutations be avoided?

What about testing using Preimplantation Genetic Testing (PGD)? PGD is not as effective as you might think because the transmission of mitochondrial DNA is not as predictable as in chromosomal DNA. The amount of mutated mitochondrial DNA transferred is variable  and sometimes it is mixed with normal mitochondrial DNA. Furthermore, depending on the mitochondrial disease you want to avoid, the threshold of inherited mutation needed to cause the disease can vary a lot. This may explain why in the same family, some children have disease symptoms and some do not. So if you could use PGD to test for mitochondrial mutations, you still might not be able to predict whether the child produced from this egg carrying the mutated mitochondrial DNA will actually get sick.

Given all we don’t know about the safety of these techniques, it will be interesting to see how the FDA and HFEA rule. Is there a way forward that safely tests these procedures or will we let IVF patients buy these as new services with little testing? Since the FDA is getting involved at this early stage, I am guessing we won’t see clinical use any time soon.

Then there are the really big ethical issues:

Should we stop trying to fix the human genome and accept the misery genetic mutations cause? Or should we invest in research to expand our understanding of these new potential treatments and reduce the possible risk to children born from these well-intentioned interventions? Is there an ethical imperative to eradicate every human disease that we can or just those diseases that are inexpensive, widespread and uncomplicated to fix?

 

 

 

 

 

 

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