A cure for people born with debilitating inherited disorders known as mitochondrial disease is now a step closer following a research breakthrough.
A large group of scientists – including teams from Oregon Health & Science University in Portland and the Salk Institute for Biological Studies in La Jolla, CA – has successfully converted skin cells from patients with mitochondrial diseases into disease-free stem cells.
In the journal Nature, they describe how they developed and tested two different but complementary cell reprogramming methods to generate mutation-free lines of stem cells from human patients with mitochondrial diseases.
The idea is that the stem cells can then be used to generate disease-free heart, brain, muscle and eye cells.
However, until stem cell technology is safe enough for transplanting into patients, in the short term, the methods are likely to be confined to research.
Senior author Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Laboratory, says the methods will be a great boon to basic research. They will help scientists examine more closely the difference between cells with mitochondrial mutations and healthy cells.
Estimates suggest around 1 in 4,000 people has mitochondrial disease, a group of inherited, chronic illnesses that arise from any one of 200 mutations in mitochondrial DNA that are passed on from mother to child. The diseases can be present at birth or develop later in life.
Mitochondria are tiny enclosures inside cells that produce energy from food. They have their own DNA that is separate from the main DNA in the cell nucleus, and unlike nuclear DNA, comes only from the egg (not the sperm).
Mutations in mitochondrial DNA leave cells without enough energy to develop and function properly. This leads to progressive, severe physical, developmental, and cognitive disabilities, with symptoms ranging from poor growth, muscle weakness, pain and loss of coordination, to seizures, blindness, hearing loss, learning difficulties and organ failure.
Treatments that can ease some of the symptoms or slow the progression of mitochondrial diseases do exist, but as yet, none can cure them.
Earlier this year, the UK took the decision to allow the creation of embryos from three people. But, while that would prevent children being born with mitochondrial disease, it does not help people who already have the condition.
To generate healthy stem cells free of mutated mitochondrial DNA, the researchers developed two techniques.
Both methods used skin samples from patients with mitochondrial encephalomyopathy or Leigh Syndrome – severe mitochondrial diseases that affect the brain and muscles.
For the first method, the team used a standard way of converting the skin cells into pluripotent stem cells – cells that have the potential to be coaxed into any type of cell in the body.
Because of the nature of mitochondrial disease, not all the mitochondria in cells are affected to the same extent. There is a chance that some will have no faulty DNA. This means in the process of generating new cells, there is a chance that some of them will end up with 0% diseased mitochondria.
This allows the scientists to pick out the 100% healthy stem cells – free of faulty mitochondria – from those generated for that particular patient.
However, this straightforward approach does not necessarily work for every patient. Some individuals do not have cells with enough, or any, mitochondria that are free of disease mutations.
So the team worked on a second approach – one similar to the mitochondrial replacement used in three-person IVF. The nucleus from a patient’s skin cell is transferred into a donor egg cell with healthy mitochondria. The new egg cell is then used to make pluripotent stem cells.
When they did this, the team discovered that the healthy mitochondria took over and healthy, genetically similar cells from the patient were successfully generated.
Co-author Jun Wu, a research associate in Prof. Izpisua Belmonte’s lab, sums up their findings:
“In either case, the idea is that we have healthy stem cells, and we know how to convert pluripotent stem cells into different cell types. They have the potential to give rise to every cell type in the body.”
Earlier this year, Medical News Today also reported how the Salk Institute team successfully demonstrated for the first time how a technique for editing mitochondrial DNA stopped human mitochondrial diseases passing from female mice to their offspring.
Prof. Izpisua Belmonte said the treatment could potentially be implemented in IVF clinics as a single injection into the mother’s egg cells or early embryos, and because it does not use donor DNA, it should lead to a safer, simpler and more ethical treatment than the three-person mitochondrial replacement therapy.