Gene Therapy Method Could Prevent Certain Inherited Diseases
October 25, 2012

Mutated Mitochondrial DNA Can Be Replaced With Healthy Copies In Human Cells

Connie K. Ho for — Your Universe Online

Researchers from Oregon Health and Science University (OHSU) recently revealed a new gene therapy method that can successfully prevent particular inherited diseases. The scientists worked under the college´s Oregon National Primate Research Center as well as the Department of Obstetrics and Gynecology at OHSU and were able to complete the procedure in human cells. With the findings of the study, the new gene therapy will provide new methods for clinical trials with human subjects in the future.

The gene therapy was originally developed as research in nonhuman primates to stop diseases associated with gene defects in the cell mitochondria.

“Previous research conducted in the Mitalipov lab in 2009 using monkey egg cells proved that this procedure was possible and that healthy baby monkeys were the result. This research illustrates that the procedure is also possible in human cells and the resulting egg cells were normal and healthy upon observation,” explained researcher Shoukhrat Mitalipov in a “Frequently Asked Question (FAQ)” section on the OHSU website.

The results of the study were recently featured in the online edition of the journal Nature as well as presented at the American Society for Reproductive Medicine Conference in San Diego this past week.

"Cell mitochondria contain genetic material just like the cell nucleus and these genes are passed from mother to infant," commented Mitalipov in a prepared statement. "When certain mutations in mitochondrial DNA are present, a child can be born with severe conditions, including diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and several other neurological diseases. Because mitochondrial-based genetic diseases are passed from one generation to the next, the risk of disease is often quite clear. The goal of this research is to develop a therapy to prevent transmission of these disease-causing gene mutations."

In the study, 106 human eggs were obtained from study volunteers from OHSU´s Division of Fertility and Reproductive Endocrinology. The team of investigators transferred the nucleus from one cell to another with the help of a method developed during another research project with nonhuman primates. The cell's cytoplasm that helps the mitochondria was “swapped out” and, by fertilizing the eggs, the researchers were able to observe whether the transfer was effective in helping the cells undergo normal development. The scientists then discovered that the method was successful in replacing defective mitochondria that had mutated DNA.

As described above, there are four steps to the new gene therapy. According to the Los Angeles Times, in the last step, the egg is fertilized when a sperm cell is injected into it and this process is known as intracytoplasmic sperm injection (ICSI). The fertilized egg would develop into blastocyts, which are early-stage embryos. If the method was developed into a treatment, the blastocysts would then be re-implanted in the womb of the mother and forms into a healthy baby.

"Using this process, we have shown that mutated DNA from the mitochondria can be replaced with healthy copies in human cells," noted Mitalipov in the statement. "While the human cells in our study only allowed to develop to the embryonic stem cell stage, this research shows that this gene therapy method may well be a viable alternative for preventing devastating diseases passed from mother to infant."

According to the article in Nature, the method was successful when the researchers utilized frozen egg cells. A health baby monkey was born as a result of the replacement of mitochondria in a frozen/thawed monkey egg cells. The second part of the study focused on preservation through freezing. After being harvested from a donor, egg cells only stay viable for a short duration of time. Freezing allowed the donor cell and the mother´s cell to be viable during the procedure. However, the process didn´t work as smoothly for human eggs as it did for monkey eggs and the scientists believe that the method was effective enough to produce a minimum of two viable embryos from each treatment cycle.

As revolutionary as this method is, it is still not approved in the United States. Science News reports that any clinical trials related to gene therapy would have to be first approved by the U.S. Food and Drug Administration. The United Kingdom has considered its use in treatment of human patients who have a higher likelihood of suffering from mitochondria-based disease. A similar study was conducted by a team of investigators based at Newcastle University, who had utilized a similar method by transferring the mother´s DNA after the egg was fertilized rather than before and the method has a lower chance of producing defective embryos.

"In the current study, about half the manipulated eggs failed to [fertilize] properly, and consequently these gave abnormal embryos,” commented Robin Lovell-Badge, a researcher at MRC National Institute for Medical Research, on the comparison between the OHSU study and the Newcastle study in an article by The Telegraph. "While these are clearly [recognizable], and could be discarded, this substantially lowers the efficiency of the procedure ... it is therefore conceivable that the other proposed method, where the nuclear genetic material is transferred after [fertilization], will be more robust."

British scientists have noted the importance of new research. Douglas Turnbull of New Castle University told the Associated Press that the findings from OHSU were "very important and encouraging.” However, he noted that “safety is an issue" if humans eventually used the technique.

As such, the researchers have attempted to not rustle any feathers in terms of the ethical concerns of the study. There are some fears that this new method will lead to “designer made babies.” Other members of the scientific community believe that the OHSU project does not deal with the same ethical concerns as cloning, and should be discussed in another context.

“To me it´s not human cloning,” Josephine Johnston, a staff member of the research institute Hastings Center that looks at the ethics of biological research, told Science News. “It´s not the creation of an individual who is genetically identical to an existing person.”

Overall, researchers believe that the recent success will affect the decision-making process on utilizing the new method with humans.

“If approved, this procedure would help families with known genetic disorders that have been previously passed from mother to child. In the past, these families had two choices: To have children with a high-likelihood of disease or families could use the adoption process. This procedure would offer families a new option where the risk of mitochondria disease is removed while maintaining more than 99 percent of the parents´ genetic information,” stated Mitalipov in the FAQ section listed on the OHSU website.

The scientists also believe that a number of steps will be taken before the method is permitted to be used on humans.

“Several steps need to occur before this procedure is used in the clinic. Additional safety and efficacy testing in patients must be conducted during clinical trials. Based on these trials, the procedure would need to be approved by the Food and Drug Administration. We also believe a public discussion about the procedure is a healthy part of this process,” continued Mitalipov in the FAQ section of the OHSU website.

The discovery of the researchers at OHSU highlights the impact of over 300 genetic diseases that can pass from mother to child due to mutated genes. A mother´s egg cells have 37 genes and thousands of mitochondria, which contain individuals DNA and provide energy to function. Defective mitochondria can pass genetic diseases from mother to child via the DNA. The new gene therapy can help prevent these diseases, as an estimated 1,000 to 4,000 U.S. babies are born with mitochondrial disease every year.