Nucleoside Therapy Explained: Why Doctors Hesitate to Treat Charlie Gard

Nucleoside Therapy Explained: Why Doctors Hesitate to Treat Charlie Gard

[Updated 2:00 pm ET — According to multiple sources, Charlie Gard’s parents have indicated that they will withdraw their legal bid in the United Kingdom to allow their son to seek experimental treatment, citing recent MRI scans that clearly show that the therapy would likely be ineffective and could lead to pain and suffering.]

With Charlie Gard — a child born with a fatal mitochondrial disease — making headlines as his parents wage a life-or-death fight with the U.K. jurisdiction, his proposed treatment, called nucleoside therapy, also has found itself in the spotlight.

Although The Telegraph reported that the family has been granted permanent resident status in the U.S. so Charlie can receive the experimental treatment, physicians and judges are still debating whether he will receive receive it.

Charlie Gard, in photo on public Facebook page
Charlie Gard, in photo on public Facebook page.

Charlie’s physicians at the Great Ormond Street Hospital (GOSH), considered to be highly experienced in treating children with mitochondrial diseases, believe the treatment will not help 11-month-old Charlie, but rather prolong his suffering, as Mitochondrial Disease News recently reported. They argue he should be allowed to die with dignity.

But his parents, along with experts from the U.S. and Italy, among others, contend there is a chance that the highly experimental treatment might improve Charlie’s condition. He is now unable to move, breathe for himself, and is thought to have extensive brain damage.

But what is this treatment that experts in the field fail to agree would be of benefit to the child with a severe mitochondrial disease?

Life’s building blocks

Our bodies’ cells hold the entire genetic code to make sure each cell does what it is supposed to do. Our DNA hold genes that, by being switched on or off, allow each cell to perform specialized functions.

But DNA can be found outside the nucleus of a cell. Mitochondria, converting nutrients to energy, hold their own DNA, needed to control the processes of cellular energy metabolism.

Each time mitochondria divide to produce new energy factories they needs to make new DNA. The same is true when DNA becomes damaged.

DNA is made up of four types of letters — G, C, A, and T. These are called nucleotides.

Charlie Gard’s mutation affects a gene called RRM2B. The gene is involved in making the four DNA letters inside mitochondria. The inability to produce the DNA building blocks causes mitochondrial depletion syndrome, the disease with which Charlie was born.

Without DNA and functioning energy-making processes, the body quickly loses its ability to function. Muscles and the brain are affected in early disease stages, because they require more energy than other organs.

Nucleosides to nucleotides

The therapy that some argue should be tried in Charlie’s case is virtually a supplementation of the missing building blocks. But, instead of giving a child nucleotides, researchers have found that the compounds turning into the four DNA letters, called nucleosides, are better to use for treatment.

When given orally, they pass the gut without being degraded, and find their way to the body’s millions of mitochondria. Since the rest of the machinery is intact, they are converted to nucleotides and can be used to build DNA, restoring the energy-making processes.

Experimental treatment

Nucleoside therapy was developed by Michio Hirano, MD, a neurologist and neuromuscular disease expert at Columbia University. While nucleoside treatment has not been evaluated in clinical trials, it has been used in 18 children with another form of mitochondrial depletion syndrome, according to an article in Scientific American.

The 18 treated patients all have mitochondrial depletion syndrome caused by mutations in a gene called TK2. In similarity with RRM2B, it is involved in making DNA building blocks.

Researchers have not publicly disclosed how the treatment has worked for the majority of these patients. But, as we previously reported, the parents of an American boy, Arthur and Olga Estopinan, have shared the story of their son’s treatment.

In similarity to Charlie, he could not move his fingers or toes or breathe unassisted. Now 6 years old, Arturito is steadily improving, and now can stand and communicate in a basic way, although he still requires a ventilator and around-the-clock care.

So, why not Charlie?

Charlie’s type of mitochondrial depletion syndrome is utterly rare. Researchers have encountered only 15 other children with the disease caused by mutations in the RRM2B gene. So, while there is some evidence of how the nucleoside treatment works in both animal models and patients with TK2 mutations, there is none for Charlie’s form of the disease — not even from mice.

Moreover, GOSH physicians claim Charlie’s brain damage is too severe to make any treatment meaningful. The damage is irreversible, they argue, and although his mitochondria will start working he will never become a functioning child.

But Charlie’s parents do not agree, and Hirano himself examined the boy and analyzed new brain scans on Monday in the search for evidence that the treatment might work.

Earlier court hearings also revealed that experts differ in how they assess the likelihood the treatment will work in Charlie’s case. The U.K. has a system in which the decision of removing life-support is based on court rulings, differing from the common practice in the U.S. to let parents decide, according to an BBC News article.

And even if a clinical trial of the treatment is on the horizon, it is unlikely that children with RRM2B mutations will be part of that study. For future children born with the more common TK2 type of mitochondrial depletion, this research might change the course of their lives.

Magdalena is a writer with a passion for bridging the gap between the people performing research, and those who want or need to understand it. She writes about medical science and drug discovery. She holds an MS in Pharmaceutical Bioscience and a PhD — spanning the fields of psychiatry, immunology, and neuropharmacology — from Karolinska Institutet in Sweden.
Magdalena is a writer with a passion for bridging the gap between the people performing research, and those who want or need to understand it. She writes about medical science and drug discovery. She holds an MS in Pharmaceutical Bioscience and a PhD — spanning the fields of psychiatry, immunology, and neuropharmacology — from Karolinska Institutet in Sweden.


  1. JJB says:

    Don’t lose hope! My daughter was also born with a novel mutation of mitochondrial disease almost 14 years ago. She was 5 weeks old when She went into heart failure. Nobody expected her to live. She will celebrate her 14th birthday next month! Hold fast to your faith. God is great, let his will be done. Cherish your little one, love heals!

  2. Shasha says:

    Butyrate helps the brain/mitochondria/gut lining etc. This may help Charlie Gard? Below is information from
    Brain Health Breakthroughs

    You may not know it, but your brain and your gut spend a great deal of time talking to one another.

    Certain chemicals in the colon are known to communicate with our central nervous system (CNS) by way of the brain-gut axis. Butyrate is one of them.

    Because high-fiber diets also increase blood levels of circulating butyrate, it’s highly likely that butyrate could directly influence the CNS, and at least one study has demonstrated a strong connection.

    Promotes Brain Health Through Gene Expression

    One of butyrate’s many functions is to influence the activity of genes.

    Proteins that play a role in gene regulation are called histones. Adding molecules called methyl groups (methylation) to histones can hold back gene activity. Adding other compounds called acetyl groups (acetylation) can increase gene activity.

    Reduced histone acetylation is characteristic of many neurodegenerative diseases. Butyrate helps maintain higher levels, thereby allowing for more gene production and better brain functioning.

    This has been demonstrated in a number of laboratory studies.

    Sodium butyrate, a form of butyrate commonly used in lab research, was shown to prevent the death of neurons in models of Parkinson’s and Huntington’s disease. It also limited brain damage and improved behavioral outcomes in stroke, and induced resistance to free radicals.

    A review by a group of researchers from New York and North Carolina found that sodium butyrate “demonstrated a profound effect on improving learning and memory, particularly in cases of disease-associated or toxicity-induced dementia.”

    In mouse models of Alzheimer’s, sodium butyrate restored histone acetylation to increase expression of learning-associated genes.

    Sodium butyrate, through its ability to increase acetylation, promotes BDNF, an important brain growth hormone; GDNF, which promotes the survival of neurons; and nerve growth factor or NGF, which regulates survival, maintenance, proliferation and growth of many types of brain cell.

    Increases Energy and Activates GPCR

    Well before memory loss shows up in Alzheimer’s, the availability of glucose is reduced, which contributes to dysfunction of the mitochondria, the cell’s energy factories.

    A number of lab studies show that butyrate can increase the activity of the mitochondria and help rectify the dysfunction that leads to neurological diseases.

    Butyrate has also been shown to switch on G protein-coupled receptors (GPCRs). These activate cellular responses to signals coming from outside the cell.

    Dysfunction of GPCRs is linked to many diseases. In fact, over 40% of prescribed drugs target them.

    Several types of GPCR can be activated by butyrate, and studies on Parkinson’s disease demonstrate that this leads to anti-inflammatory effects in the brain.

    The conclusion of the review by US researchers was that butyrate had “significant potential as a therapeutic for the brain” and to improve outcomes in patients with neurological disorders.

    Best Food Sources of Butyrate

    All high-fiber foods will be a source of butyrate, but some of the best are resistant starches found in whole grains, oats, rice, beans and other legumes.

    Fructo-oligosaccharides in bananas, onions, leeks, Jerusalem artichoke, sweet potatoes and asparagus are also excellent at allowing butyrate-producing bacteria to thrive.

    Milk also contains butyrate, with butter being the richest dietary source. The nutrient is also found to a lesser extent in plant oils.
    Lee Euler

  3. Andrew W says:

    Just a couple of facts – you claim that “experts from the U.S. and Italy, among others” think the treatment would help Charlie. Except that those people comprise a minority of experts, and none of them had either examined Charlie or seen any of his scans before pronouncing that the treatment could help. Your ‘among others’ makes it sound like lots of experts agree with Hirano – in fact the ‘others’ are simply a load of non-experts.

    You report that “Hirano himself examined the boy and analyzed new brain scans on Monday in the search for evidence that the treatment might work.” That makes it sound like Hirano has been involved in the case up to now. In fact he has only just examined Charlie and, going from the response of the parents, has clearly concluded that his treatment wouldn’t help after all.

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