Controversies concerning mitochondrial replacement therapy

Abstract

Research on mitochondrial replacement therapy (MRT) holds the promise of helping women who have, or are at risk of transmitting, mitochondrial disease, but has recently been blocked by the Food and Drug Administration (FDA). Thus, several critical ethical and policy questions arise. Mitochondrial disease can be devastating for those who have it. Yet existing treatments remain supportive rather than curative. Women confronting this disease have a high chance of having an affected child and limited reproductive alternatives. Recently, US and British researchers have been developing MRT in animal models as a way of possibly preventing inheritance of mitochondrial mutations. MRT offers women with mitochondrial disease the chance to have a genetically related child without mitochondrial disease by placing the nuclear DNA from the mother's egg into a donor egg that has no identified mitochondrial mutations. Researchers are investigating two MRT techniques: pronuclear transfer and maternal spindle transfer, both of which, if successful, would result in an embryo whose nucleus is formed by the normal mixture of two parental gamete nuclei but whose mitochondrial genome is from a third individual. Many scientists and patient advocacy groups have thus called for MRT trials in humans. The UK government has published draft regulations for consultation that would allow clinical trials of MRT (1). Such trials would presumably be observational studies of outcomes after intervention. The number of participants would be limited until initial data are analyzed on those with the highest risk of transmitting severe mitochondrial disease. In the United Kingdom, only 10 applicants are predicted to be eligible per year (1). Data could subsequently be gathered and analyzed through birth onward to demonstrate that mitochondrial mutations or other major abnormalities are not transmitted. These offspring would then be followed over time. Ideally, their eventual offspring would be studied as well. Pending the results of the initial phases of this study (e.g., observations of infants born using the procedure), MRT could potentially be performed and studied with additional participants with appropriate careful follow-up as well (i.e., 40 or more years of longitudinal multigenerational study would not necessarily need to be completed before performing and studying MRT on additional participants). In the United States, the FDA met in February 2014 and collected comments through May 2014 and has suggested that it will continue to ban human trials. Here we discuss the arguments offered against studies of MRT and provide reasons why clinical studies are ethically justified.