FDA Considers Mitochondrial DNA Replacement

Ricki Lewis, PhD

February 26, 2014

The Cellular, Tissue, and Gene Therapies Advisory Committee of the US Food and Drug Administration (FDA) met February 25 to consider the safety of human testing of mitochondrial manipulation technologies to prevent mitochondrial disease and to boost fertility in older women. The technologies combine DNA from 3 individuals in a fertilized ovum.

Invited experts discussed preclinical evidence to inform design of early-phase clinical trials. Although comments will be collected until May 9, a consensus emerged that better understanding of mitochondrial biology may be a necessary shorter-term goal.

Complex Genetics

Gerald Shadel, PhD, director of pathology research at the Yale School of Medicine, New Haven, Connecticut, colorfully began by defining mitochondria as "double-membraned submarines that cruise around cells but are actually very complex, forming large, elaborate dynamic networks." Each of a cell's many mitochondria houses several copies of its tiny genome.

Most human cells are heteroplasmic: Different mitochondria within the same cell may have either of 2 variants of a particular gene. A mutation may need to exceed a threshold in many cells to cause disease, which means that a woman's mutational load may be too low to affect her health, but her child might inherit a collection of variants above the threshold and be ill.

Women exclusively transmit mitochondria because the organelles are not in the sperm head, and the rare sperm that do enter an oocyte are destroyed. The mitochondrial genome consists of 37 genes, 13 of which encode proteins, and the remainder of which encode transfer RNA or ribosomal RNAs.

Mitochondrial diseases reflect the organelle's abundance in muscle; symptoms include fatigue, weakness, exercise intolerance, and characteristic "red ragged" fibers. The conditions may also affect the liver, kidneys, endocrine system, brain, lungs, and vision. "The heterogeneity of these disorders is simply astounding," Salvatore DiMauro, MD, a neurologist at Columbia University Medical Center, New York City, told the group. Mitochondrial diseases include MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa), and Leigh syndromes. The prevalence of the diseases is about 1 in 10,000.

Techniques Transfer Spindles or Pronuclei

Shoukhrat Mitalipov, PhD, senior scientist at the Oregon National Health & Science University in Portland, and colleagues delivered mitochondria to 7 rhesus macaques by transferring spindles from healthy oocyte donors, to which the organelles cling. Discovery of spindle problems in the oocytes of older women suggests that mitochondrial technology will not help age-related infertility. A second approach to replacing mitochondria introduces the male and female pronuclei from a fertilized ovum into an enucleated donor oocyte.

Dieter Egli, PhD, senior research fellow at the New York Stem Cell Foundation in New York City, described human swapped pluripotent stem (swaPS) cells that place a nuclear genome in different oocytes. His team used the cells to address several concerns about mitochondrial manipulation.

Culturing and observing swaPS cells for a year so far has demonstrated that heteroplasmy, nuclear-mitochondrial incompatibility, "carryover" mitochondria from the nucleus donor, epigenetic modifications, and chromosomal abnormalities do not appear to be problems, at least in the cells and their differentiated daughters.


The United Kingdom is ahead of the United States in the mitochondrial regulatory arena. A review panel convened in 2011 started the discussion of allowing mitochondrial DNA replacement as an exception to the ban on germline manipulation because it is the only way to circumvent mitochondrial conditions to enable a woman to have genetic children.

In 2013, the UK panel dropped infertility because of the spindle problem and considered results on nonhuman primates no longer critical because of findings in human cells. UK regulators will introduce a draft law this spring.

The FDA's caution may reflect its 2001 halt of a New Jersey fertility clinic's injecting cytoplasm from fertile women into the eggs of 17 infertile women before in vitro fertilization. "Ooplasm transfer was spreading into clinical practice in the US, and [the] FDA had a concern about the risk to any children resulting from mitochondrial transfer," said Deborah Hursh, PhD, biologist with the Office of Cellular, Tissue and Gene Therapies at the FDA. One child had a chromosome missing, and another had autism.

A few attendees asked whether mitochondrial replacement was necessary, or whether adoption or oocyte donation could suffice. Another echoed point was that the proposed intervention does not treat a patient but, instead, creates one. Sharon Reeder provided a patient's view. "I've been sitting here thinking, wouldn't it be great if all this research was about therapies to help those of us whose lives are severely affected by mitochondrial disease?"

Katharine Wenstrom, MD, professor of obstetrics and gynecology at the Alpert Medical School of Brown University, Providence, Rhode Island, spoke for many. "There are so many aspects of mitochondrial disease that we don't understand: tissue specificity, changes over time, response to environmental stimuli."

Chair Evan Snyder, MD, PhD, professor in the Stem Cells and Regenerative Biology Program at the Sanford-Burnham Medical Research Institute, La Jolla, California, summed up the day: "At this point, there probably aren't enough data in animals or in vitro to conclusively move on to human trials without answering a few additional questions."

The voting members have disclosed no relevant financial relationships.

Cellular, Tissue and Gene Therapies Advisory Committee Meeting, February 25, 2014.


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