Gene Therapy Shows No Long-Term Harm in Animals: Study

FRIDAY, Dec. 11, 2020 (HealthDay News) -- Results from a long-term study of a gene therapy technique to prevent inherited mitochondrial disease show promise, researchers say.

Studies of the technique at Oregon Health & Science University in Portland show no adverse health effects in rhesus macaque monkeys and their offspring. The researchers said the technique could break the cycle of disease passed from mother to baby through mutations in mitochondrial DNA (mtDNA).

Though results of animal studies sometimes differ in humans, the findings bolster the scientific basis for mitochondrial replacement therapy (MRT) in human clinical trials, the study authors said.

But they added a key caveat: The study found varying levels of mtDNA from the mother that replicated and built up within some internal organs. It was not enough to cause health effects, they noted in a university news release.

"Our data show that MRT is compatible with normal development, fertility and aging in nonhuman primates without any detected adverse effects," the authors reported. "However, carry-over maternal or paternal mtDNA contributions increased substantially in selected internal tissues/organs of some MRT animals, implying the possibility of mtDNA mutation recurrence."

The findings were published online Dec. 8 in the journal Human Reproduction.

Mitochondria exist in nearly every cell of the body, according to the United Mitochondrial Disease Foundation. When they are unable to convert food and oxygen into energy throughout the body, organ systems begin to fail and even stop functioning.

The therapy under investigation replaces disease-causing mutations in a mother's egg with donor mitochondria.

The researchers said the first five monkeys born in 2009 at OHSU's Oregon National Primate Research Center with the aid of the technique all developed normally to adulthood. Their offspring did, too.

"It's reassuring that the monkeys appear to be healthy and fertile through generations," said co-author Dr. Paula Amato, professor of obstetrics and gynecology at OHSU School of Medicine. "It adds to a growing body of evidence that would support moving forward with clinical trials to prevent the transmission of mitochondrial disease."

The study offered insight about the amount of maternal mtDNA detected within organs -- a potential problem in cases where the technique is intended to prevent transmission of disease-causing mtDNA from mother to child. That's because as cells divide, this small remnant can preferentially replicate as the embryo develops, potentially causing the disease the therapy aims to prevent.

The investigators found varying amounts of mtDNA in cell samples, from 3% in blood, urine and skin cells to 16.6% in the small intestine. This is below the 60% level that would be considered disease-causing, they explained.

It is also irrelevant in cases where the technique is used to treat infertility instead of preventing disease transmission, the team noted.

The researchers also found paternal mtDNA in cells of two monkeys, which they called unusual but not unprecedented.

Shoukhrat Mitalipov, director of the OHSU Center for Embryonic Cell and Gene Therapy, said he is interested in learning more about why the minute level of mtDNA in sperm cells replicated exponentially as the embryos grew.

"The question was always there about the long-term safety of this technique," Mitalipov said. "We wanted to find out whether this procedure will somehow show negative effects later in life. We saw no adverse health effects across two generations."

Though clinical trials are ongoing in the United Kingdom and Greece, the U.S. Congress has barred the U.S. Food and Drug Administration from providing oversight for such trials in the United States.

More information

The National Human Genome Research Institute offers more on mitochondrial DNA.

SOURCE: Oregon Health & Science University, news release, Dec. 8, 2020