Bone marrow transplants offer an unexpected way for diseased cells in the heart and brain to get replacement parts, a Stanford Medicine-led study has shown. The finding offers hope for the first effective treatment of mitochondrial disorders, a group of genetic diseases in which cells’ motors, called mitochondria, are dysfunctional.

The study, published in Nature Communications, focused on a mitochondrial disorder called Friedreich’s ataxia. In mice with the condition, providing a bone marrow transplant had a surprising benefit: After transplant, healthy immune cells took up residence in tissues around the body, then handed off their mitochondria to neighboring cells whose mitochondria were failing, partially alleviating disease symptoms.

“It’s a way to use the blood system to treat nonblood organs,” said senior study author Natalia Gomez-Ospina, MD, PhD, assistant professor of pediatrics. Although it’s been known for more than a decade that cells can give mitochondria to their neighbors, the reasons they do so are unclear, Gomez-Ospina said.

“It’s profound,” she said. “Cells are talking to each other in ways that are more consequential than we’ve realized, and this has many implications for disease treatment.”

The study’s lead author is Hyunmin Cho, PhD, who was a postdoctoral scholar at Stanford Medicine when the study was conducted.

Barriers to gene therapy

Mitochondrial disorders affect about one in every 5,000 people. These genetic diseases interfere with the function of mitochondria, the cells’ engines, hampering their ability to transform large, energy-rich molecules like glucose into small packages of energy (known as adenosine triphosphate, or ATP) that power all aspects of life.

Although mitochondrial diseases can be diagnosed at any age, many first appear in childhood. They affect the entire body, hitting hardest in organs that use a lot of energy, including the heart and brain. Mitochondrial diseases vary in severity but are typically degenerative, with the worst types leading to death in childhood or young adulthood. The current treatment is high doses of antioxidants, which reduce damage from poorly functioning mitochondria but do not address the underlying problem.

A few clinical trials are testing gene therapy for mitochondrial diseases; however, the approach has several pitfalls, Gomez-Ospina said. The disorders are caused by a wide variety of mutations, meaning gene therapies would need to be developed and tested one at a time. Some of the mutations responsible for these diseases are in the nuclear DNA, whereas others are in the mitochondrial DNA, which scientists have no reliable way to edit. Delivering corrected genes to organs throughout the body is also tricky; most gene therapies use viral vectors to provide corrected genes, but getting many copies of a virus to disperse evenly throughout the body would be nearly impossible, especially when they need to reach tissues behind the blood-brain barrier.

Friedreich’s ataxia is a mitochondrial disease affecting one in every 40,000 people worldwide. It causes neurodegeneration and progressive problems with coordination and walking. Heart failure is the main cause of death. Gomez-Ospina’s team decided to see whether a modified bone marrow transplant could help treat Friedreich’s ataxia. They tested the concept in a mouse model.

Hitching rides into the heart and brain

In a conventional bone marrow transplant, aka a stem cell transplant, patients’ own blood-forming stem cells and immune cells are first eliminated with radiation or chemotherapy. The patient then receives bone marrow from a healthy donor. Stem cells from the donor take up residence in the patient’s bones and begin generating healthy blood and immune cells. The procedure is usually used for people with blood cancers, as well as genetic diseases that damage immune function or the body’s ability to make blood.

In the new protocol, researchers used a powerful pre-transplant conditioning method that eliminated not only bone marrow but also immune cells throughout the body. All tissues have resident immune cells – called microglia in the brain and macrophages in other parts of the body – which serve as a first line of defense against viruses, bacteria, and other pathogens.

The study showed that, after the bone marrow transplant with the new conditioning protocol, tissue-resident immune cells in the brain and heart were replaced by healthy cells derived from the donated bone marrow.

“For instance, the brain can say, ‘Uh oh, my microglia have been depleted. Let’s repopulate them from the bone marrow,’” Gomez-Ospina said. “We can leverage that process to get healthy cells into the brain.”

These replacement immune cells distribute themselves much more evenly than any artificial system for delivering drugs or viruses ever could, she added. “These cells, by their nature, crawl everywhere, migrating dynamically throughout the central nervous system, including into deep brain nuclei. And they’re constantly touching all kinds of other cells.”

Healthy mitochondria reduce symptoms

By labeling the donated bone marrow with two types of fluorescent markers – green for the cells themselves and red for their mitochondria – the researchers showed that the donor immune cells were handing off their mitochondria to adjacent, diseased cells in the brains and hearts of the mice they studied.

Data from the central nervous systems of treated mice showed that many cell types took up the healthy mitochondria, with highest uptake by microglia; macrophages; neurons; and oligodendrocyte precursor cells, a type of brain cell that supports neurons.

The researchers measured changes in gene pathways in cells that took up donor mitochondria. In the central nervous system cells they assessed, cellular pathways linked to ATP production and oxidative phosphorylation – mitochondrial jobs – were turned up, offering evidence that the healthy mitochondria go to work after they are handed off from the donated immune cells to neighboring diseased cells. In cardiac cells, the researchers saw a decrease in gene pathways linked to heart muscle damage, including less activation of genes associated with fibrosis and oxidative stress.

The mice with Friedreich’s ataxia that received new bone marrow also experienced partial resolution of many of their symptoms, the study found. Compared with mice that had untreated Friedreich’s ataxia, the treated mice showed less loss of fur, better growth, and improved survival. They exhibited better coordination and muscle strength, and they spontaneously walked farther than untreated mice. Echocardiograms showed healthier heart structure and better blood pumping in treated than in untreated mice.

Potential for other mitochondrial disorders

The researchers suspect that mitochondrial transfer from healthy immune cells could ameliorate a wide variety of mitochondrial disorders, Gomez-Ospina said.

“It’s a potential therapy for Friedreich’s ataxia, and it could be a path to treatments for other, even more severe mitochondrial disorders in which patients have only a few years to live,” she said. “If I had infinite resources, I would pick a bunch of mitochondrial diseases and do the same study in those conditions.”

The results also open the possibility of a treatment that combines bone marrow transplant and gene editing. If patients’ own blood-forming stem cells were removed from the body, edited to include the corrected gene, and returned to them via transplant, the corrected mitochondria could piggyback around the body on immune cells, providing a workaround for the challenge of reaching every cell in the body.