The Experimental Therapy Charlie Gard's Parents Are Fighting For, Explained

Nucleoside bypass therapy is highly experimental and has never been used on someone with Charlie's rare mitochondrial disease, but it has also shown promise in some cases.

“Charlie’s brain, muscle and ability to breathe are all severely affected. In addition, Charlie has congenital deafness and a severe epilepsy disorder,” the hospital says on its website. “Charlie has severe progressive muscle weakness and cannot move his arms or legs or breathe unaided. Charlie's eyelids cannot stay open and his eyes point in different directions because of muscular weakness.”

Charlie’s case received wide notice when his parents, Chris Gard and Constance Yates, disagreed with the hospital’s assessment that he should be taken off life support. Their case has been heard in several UK courts, most recently in Britain’s High Court this week. While the hospital advocates transitioning Charlie to end-of-life palliative care — officials have stated that “he has no quality of life and no real prospect of any quality of life” — his parents want him to undergo a highly experimental treatment in the United States called nucleoside bypass therapy.

The courts have so far sided with the hospital, which believes the treatment is unjustified given the Charlie’s irreversible brain damage. “If there is important new evidence that suggests my decision should be changed then I will change it,” said High Court Justice Nicholas Francis, who is overseeing an appeal of the case.

Pope Francis and US President Donald Trump have both expressed support for the wishes of the family, raising the profile of the case. The hospital, meanwhile, is barred by the High Court’s ruling from transferring Charlie to the US for treatment. “This is not an issue about money or resources, but absolutely about what is right for Charlie,” it said in a statement.

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“Mitochondrial disease” is an umbrella term for many different diseases. Though mitochondrial diseases may have different symptoms, they all stem from malfunction or failure of the mitochondria, an essential organelle that creates energy within a cell. It is estimated that one in 5,000 people have a mitochondrial disease, according to Dr. Bruce Cohen, director of the NeuroDevelopmental Science Center at Akron Children’s Hospital and an expert in mitochondrial diseases.

Charlie’s MDDS is caused by mutations in the RRM2B gene. The same syndrome can also be caused by mutations in other genes, including the TK2 gene. Charlie's specific mutation so rare that there are only three other people in the world with the same disease, according to his parents’ barrister.

Mitochondria are popularly known as cell “powerhouses,” but that’s a very simplified definition. In reality, they are complex and indispensable parts of almost every eukaryotic cell. (All multi-cell organisms are made of eukaryotic cells; the other type of cell, prokaryotic, is found in single-cell organisms.)

One of the main functions of mitochondria is to break down food nutrients using oxygen and convert them into adenosine triphosphate (ATP), the energy currency of cells. ATP is what allows our body to function, and is critical to the brain, heart, and other muscular organs. And just as mitochondria help to give us life-sustaining energy, they also play a key role in cell death, called apoptosis.

Mitochondria are unique among organelles — they operate like a cell within a cell, and have their own set of DNA (called mtDNA). Mitochondrial diseases occur when there is a mutation in mtDNA that impairs the function of the mitochondria.

“Most of these diseases, result in the inability of the mitochondria to replicate itself enough,” Cohen told Seeker. Even if it does replicate, he said, it would be a damaged copy.

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There are hundreds of types of these diseases, some more serious and rare than others. Cohen’s patients have ranged from severely disabled infants to middle-aged adults with minimal symptoms. Common symptoms include muscle weakness, seizures, developmental delays, and eventual death. There is no known cure for any mitochondrial disease.

There are, however, experimental therapies in development — and Charlie’s parents have pinned their hopes on one of them. Specifically, they want their child to undergo nucleoside bypass therapy, a treatment that Cohen called “highly experimental” and which he noted would not work on all mitochondrial diseases.

But it could theoretically work on Charlie — not as a cure, but as a measure that might be able prevent more damage from happening and potentially forestall his death.

MDDS, Charlie’s form of mitochondrial disease, involves the production of nucleosides, one of the building blocks of mtDNA. The presence of nucleosides is “highly regulated” within the mitochondria, Cohen explained. Anything that messes up the concentration of nucleosides can result in not being able to produce mtDNA.

Nucleoside bypass therapy, which was developed by Dr. Michio Hirano of Columbia University Medical Center, involves an oral dose of extra nucleosides that rebalances the concentration of these essential building blocks inside the mitochondria. The dose is in a form that protects the nucleosides from breaking down in the gut. Hirano and his colleagues published a paper in 2014 that showed that nucleoside bypass therapy was successful in mice with a different form of MDDS than Charlie (theirs was caused by TK2 gene mutations). The treatment prolonged their life — but only for about a month.

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Nucleoside bypass therapy has only been used on one human patient in the US, a young boy named Art Estopian Jr., who also developed MDDS from TK2 mutations. His disease is similar to Charlie’s, though his symptoms are less severe. Though the therapy has not been approved by the FDA, Art was treated through a compassionate use request. With the treatment, he has been able to live years longer than doctors predicted, and is now six years old. But even so, Art has yet to breathe without a ventilator or walk on his own.

Art’s parents are strong advocates for the treatment, and have publicly supported the efforts of Charlie’s parents to have their child come to the US to receive the same therapy. Meanwhile, medical professionals and the judge presiding over the parents’ appeal have noted that the therapy has never been tried on mice or any humans with Charlie’s specific gene mutation, which was first recognized in 2007. Some experts, including a group of doctors in Italy, have pointed to potential “dramatic clinical improvements” in making the case for the treatment.

Regardless of what happens in Charlie’s case, Cohen says that this controversy highlights how little is known about mitochondrial diseases. Mitochondria also play an important role in much more common ailments, including Alzheimer’s disease, diabetes, and even cancer.

“If we understood the mitochondria,” Cohen said, “we would really be well on our way to understanding a lot of these horrible disorders.”

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