Charlie Gard and Mitochondrial DNA Depletion Syndrome
Over the last few months, the international media has been following the situation of 11-month old Charlie Gard and his parents, as they fight a legal battle on behalf of their son. Charlie, a patient at Great Ormond Street Hospital (GOSH) in London, suffers from a condition called Mitochondrial Depletion Syndrome (MDS), also known as Mitochondrial DNA Depletion Syndrome, and is now being kept alive by life support that helps him breathe.
The controversy has arisen because of a disagreement between the hospital and Charlie’s parents over how their son’s treatment should continue. GOSH believe that Charlie has no chance of survival or recovery, and therefore wish to take him off life support to allow him to die peacefully. In contrast, Charlie’s parents have been fighting for permission to take their son to the USA to undergo an experimental treatment, even raising £1.3M ($1.7M) to pay for the therapy, in the hopes that it will improve their son’s condition.
After taking the case through multiple different courts, the UK Supreme Court ruled in favour of GOSH at the beginning of June. Near the end of the month, the parent’s again were denied their wish when the European Court of Human Rights refused to intervene in their case, upholding the ruling of the Supreme Court.
What many of the news articles covering the situation do not include, however, is an explanation of what Charlie’s condition entails or what the experimental treatment his parents want to transfer him for is. To that end, we took a look at MDS and nucleoside bypass therapy and broke them both down for you.
What is Mitochondrial Depletion Syndrome?
Mitochondria are structures within cells that are responsible for oxidative phosphorylation, the chemical process that converts oxygen into the energy molecule ATP, more commonly known as respiration. Unlike other sub-cellular structures, mitochondria possess their own DNA that is external to the nucleus and which accounts for around 1% of the cell’s total genome. The production of this mitochondrial DNA (mtDNA) is regulated by an enzyme called ribonucleotide reductase (RNR) which helps to produce the nucleotide building blocks of mtDNA.
MDS is a term that actually refers to a number of autosomal, recessive conditions, all of which are linked by a significant drop in the quantity of mtDNA. The lack of mtDNA negatively impacts the activity of mitochondria within the body, causing abnormally low ATP levels and reduced energy. Generally beginning in early infancy, these decreased ATP levels lead to gradual muscle weakness and can also affect different organs within the body, depending on the type of MDS.
Charlie Gard has a form of MDS that is caused by a genetic mutation in the RRM2B gene. The mutation causes the characteristic muscle weakness of all MDS cases, alongside brain and kidney damage. At present, it is unclear why the kidneys or the brain are affected by the condition, but it is thought that it might be related to the high energy demands of the organs leading them to being affected more heavily than the rest of the body. In most cases, the condition results in death during early infancy, as weakening of the intercostal muscles causes respiratory failure.
In healthy people, the RRM2B gene is responsible for making a subunit of RNR called the p53 inducible small subunit (P53R2). In patients like Charlie who do not have a functional RRM2B gene, the mutations lead to reduced activity or decreased quantities of RNR which impairs production of nucleotides for mtDNA. Without sufficient nucleotides, cells have less mtDNA and their mitochondria cannot function correctly.
It’s believed that only 16 children in the world have RRM2B-related MDS, Charlie Gard being one of them. Because of the intense rarity of the condition, there are currently no widely available treatments for patients like Charlie. There is, however, an experimental therapy being offered by researchers in the USA known as Nucleoside Bypass Therapy and it is this treatment that Charlie’s parents are trying to get for their son.
Nucleoside Bypass Therapy (NBT)
Also known as deoxypyrimidine monophosphate bypass therapy, NBT works by providing an oral medication that contains the naturally occurring compounds that MDS patients cannot produce themselves. The pill, which has to be taken daily, provides patients with deoxythymidine monophosphate (dTMP) and deoxycytidine monophosphate (dCMP); as it requires continual treatment, the therapy cannot be considered a ‘cure’.
The treatment has already been used to treat 18 MDS patients with some level of success, which is why it has been considered so carefully for Charlie’s case. However, experts involved in the court cases have highlighted a number of reasons why the treatment might not be suitable in this instance, contributing to the court’s decision to refuse the transfer.
The primary problem is that while the treatment has seen success in the past, it has never been tested against RRM2B-related MDS in any animal, including mice. Typically, the treatment has been used against a different form of MDS that results from thymidine kinase 2 (TK2) deficiency and even in those cases, the patients were not as deeply affected as Charlie. TK2-related MDS doesn’t have the effect on the brain that RRM2B-related MDS does, and thus there is no evidence that the drug treatment has the ability to cross the blood-brain barrier. Without that ability, the treatment would not be able to resolve Charlie’s brain damage and would be unsuccessful.
Taking these factors into account, the UK judiciary system has repeatedly ruled in favour of GOSH when considering Charlie’s future. On Friday, doctors at the hospital applied for another hearing in the UK High Court in response to new evidence from Rome about the effectiveness that NBT may have in Charlie’s case and this morning, the application was accepted. While the exact nature of the evidence remains unknown, GOSH have stated that it might raise Charlie’s chance at recovery from 0% to 10%. However, until the case is put before the court, there’s no way of telling how accurate that statement is.