Mito Disease Research: New Prevention Strategy

A new assisted-reproduction strategy may prevent transmission of mitochondrial disease

by Quest Staff on August 28, 2009 - 10:18am

Scentists at Oregon Health and Science University in Portland have developed an assisted-reproduction technique that has the potential to allow mothers with mitochondrial myopathies and other mitochondrial diseases to virtually eliminate the risk of passing on the disease to their children.

Masahito Tachibana and colleagues, who published their findings online Aug. 26, 2009, in the journal Nature, announced the new technique recently resulted in the births of four healthy rhesus macaque monkeys. Shoukhrat Mitalipov coordinated the study team.

About mitochondrial diseases

The mitochondria are the energy-producing units inside almost all the body's cells. They're especially important in high-energy cells, such as those of the muscles and nervous system. Mitochondria have their own DNA ("mitochondrial DNA"), which coexists with the main source of DNA in cells, the chromosomes in the nucleus ("nuclear DNA"). Mitochondrial diseases can result when this DNA contains mutations.

Each child inherits half his or her nuclear DNA from the father, through a sperm cell; and the other half of his or her nuclear DNA from the mother, through an egg cell. However, all of a child's mitochondrial DNA comes from the mother, from her egg cell.

Since 1988, it's been known that mutations in mitochondrial DNA, like mutations in nuclear DNA, can cause disease. But the level of severity of the disease, when it's transmitted from parent to child, is highly unpredictable.

That's because each egg cell contains an assortment of mitochondria, some of which harbor the disease-causing mutation and some of which do not. The severity of the child's disease depends on the percentage of mutated mitochondrial compared to normal mitochondrial DNA he or she inherits through the egg cell.

Mitochondrial DNA mutations, if present in high enough concentrations in a person's cells, can affect the nervous system, causing seizures, developmental delays, deafness, vision defects, poor balance, and strokes. Mutations also can affect the skeletal muscles, causing weakness and exercise intolerance; the heart, causing cardiac abnormalities; and the liver, kidneys, digestive tract and pancreas, causing malfunctions in those organs.

The severity of a mitochondrial disease in a child depends on the precentage of abnormal (mutant) mitochondria in the egg cell that formed him or her.

About the new findings

Recent advances in genetic technology have made it possible for many DNA mutations to be diagnosed prior to pregnancy. This strategy, called "preimplantation genetic diagnosis," involves fertilizing an egg cell from the mother with a sperm cell from the father in a laboratory dish ("in vitro fertilization"); analyzing the DNA from the resulting embryo when it contains some five to eight cells; and implanting an embryo after it has been determined to be mutation-free. (See "The Pain and Promise of Newborn Genetic Diagnosis.")

So far, preimplantation genetic diagnosis has been used almost exclusively to diagnose mutations in nuclear DNA. Mitochondrial DNA mutations can be diagnosed in a laboratory from a mother's egg cell, but until now, the steps between diagnosis and implantation have been uncertain.

One strategy that's been tried is injecting cellular material containing nonmutated mitochondria into an egg cell before it's fertilized, a technique called "cytoplasmic transfer." But the amount of normal mitochondiral DNA that can be transferred by this method is limited, and the technique can damage the receiving cell.

Another possibility is transferring the DNA-containing nucleus from a mother with a mitochondria mutation to an egg cell without a nucleus but with normal mitochondrial DNA.

monkey twins
Healthy monkey infants "Mito" and "Tracker," named after a dye called "Mitotracker" used to detect mitochondria in cells, are male twins born using spindle transfer. A total of four healthy monkeys have been born using this new technology.

That approach, called "nuclear transfer," has been deemed unfeasible because of the high risk of damage to the chromosomes in the nucleus during the transfer.

The new technique described in Nature appears to have overcome this barrier. The scientists perfected the technique in monkey eggs and sperm cells, which are very similar to human ones.

First, they extracted a structure called the "spindle-chromosomal complex" from an egg cell taken from a mother with a mitochondrial DNA mutation. They then transferred the complex to an egg cell with healthy mitochondria but no nucleus of its own. After fertilizing the cell with sperm in a laboratory dish, the researchers transferred the fertilized embryo into the uterus of a "surrogate mother" monkey. (In humans, the woman donating her nuclear DNA would, in most cases, receive the fertilized embryo.)

The spindle-chromosomal complex protects the chromosomes from damage during the transfer from one egg cell to another, and it can be separated cleanly from the donor cell, ensuring few, if any, donor mitochondria accompany it.

Meaning for patients

If it proves safe and effective in humans, the new strategy could provide a way for women with disease-causing mitochondrial DNA mutations to undergo in vitro fertilization using their own nuclear DNA and their partner's nuclear DNA but using donor mitochondrial DNA. An embryo resulting from this type of in vitro fertilization would reflect the genetic heritage of its parents almost entirely (minus only the mother's mitochondrial DNA) and would ensure that the disease-causing mutation would be absent.

Availability of spindle transfer for patients is probably at least a few years away.

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