Baby Charlie Gard — a Scientist’s View to Mitochondrial DNA Depletion Syndrome

Motivation for this blog. During the past few weeks I have been asked to comment the situation and therapy of a British baby, Charlie Gard, suffering from a rare infantile mitochondrial disorder. I work in Finland and know of his situation second hand, from publically available sources. I have no role in his treatment or the ongoing debate. However, my expertise is in mitochondrial diseases, especially in those that Baby Charlie has. Scientific knowledge of the condition is what I can deliver.

Background: Baby Charlie Gard suffers from a rare mitochondrial disease called mitochondrial DNA depletion syndrome. As the disease is devastating and fatal, his story is extremely tragic and has touched the hearts of people around the world. Even the Pope and President Trump have actively offered their help for the Charlie’s parents, who are fighting to get their baby treated with an experimental therapy, in development in the United States. However, the treating doctors — world-leading experts on mitochondrial disease — in Britain have said that such a therapy cannot cure the severe brain damage that Charlie has developed, and the therapy might only extend the suffering of the baby. The British court agreed with the experts and has not supported the parent’s appeal to transport Charlie to US. The court case continues this week.

What is mitochondrial DNA depletion syndrome?

Mitochondrial DNA depletion syndrome (MDS) is one of the most severe forms of infantile disorders. It is caused by recessive nuclear genome defects, meaning that both the mother and father carry the gene defect, and the child may manifest the disease only if he/she inherits it from both the parents. The defect results in depletion of DNA building blocks, nucleotides (A, T, G or C, as we learned at school) in cells. In tissues, such as muscle, consisting of non-proliferating cells (whereas for example blood cells do proliferate), these nucleotide pools are serving mainly mitochondrial DNA (mtDNA) maintenance. If the proteins that make A, T, G and/or C are defective, mtDNA is lost in the affected tissue and MDS disease manifests.

Mitochondria are the cellular engines, using nutrients and oxygen to transform the energy of nutrients for cellular energy and provide growth ingredients for cells. Therefore loss of mtDNA is rapidly fatal — the engines of the cells fail.

The children with MDS are born apparently healthy, but during the first months or years of life, they start to deteriorate rapidly and may die even in a few months of time. Depending on the nuclear gene defect underlying the specific disease in a child, different tissues may manifest with MDS. If G-nucleotide cannot be made (dGK dysfunction), a severe liver disease will manifest. If T-nucleotide cannot be made (TK2 dysfunction), a rapidly progressive muscle weakness and degeneration occurs, called muscle-specific MDS. The condition leads to complete loss of muscle power, including the respiratory muscles, and rapidly fatal disease course. In the case none of the nucleotides can be made (RRM2B dysfunction), an early-onset multiorgan failure results. According to public sources, Baby Charlie has this most severe form of MDS, affecting all non-proliferative tissues, including the brain. All forms of MDS are incredibly tragic diseases.

Recent development in therapies — slight glimmer of hope?

Recently, American and Spanish researchers reported promising results from mice having TK2 defect, modeling the muscle-specific MDS. When the scientists fed the mice with a mixture of nucleotides A, T, C and G, the lifespan of the mice increased, although they still died prematurely. Also cultured MDS patient cells showed improvement of disease findings. The approach was named nucleoside bypass therapy. The beneficial effects in mice were quite surprising and exciting, as scientists had previously thought that nucleosides cannot survive the acidic and enzymatic environment of the stomach and gut — and even if they did, they would be unlikely to enter the cells. However, the nucleotides did indeed make their way to tissues and even improved the condition of the sick mice with muscle-MDS.

Can an experimental therapy be brought to human patients?

The nucleotide bypass therapy was promising in mice, but how could it be developed to benefit the patients? Typically new therapies go through strict testing first in healthy controls (Phase 1), then in patients (Phase 2–4). The process takes years, and the steps 2–4 need a large amount of patients, a lot of red tape and funds. However, for rare and rapidly lethal diseases, such as MDS, large patient cohorts are not available for trials. For such disorders, if promising therapies are in development, supported by strong experimental data from for example mice, the therapy can be given to patients in strictly controlled conditions, including ethical approval. This is called compassionate use.

Based on the preliminary mouse results, compassionate use was applied for some patients with the muscle-manifesting MDS(TK2). The disease manifests during the first few months or years of life, and the untreated disease is rapidly fatal. Because of the weakness of respiratory muscles, some patients have been connected to mechanical ventilation and may live for several years, but gradually lose all muscle power. Some neurologists have decided not to connect the children to mechanical ventilation at all, because this will only extend the suffering with no hope for recovery.

However, according to preliminary results, when some TK2-MDS patients were fed with nucleotides A, T, G and C based on compassionate use, disease signs ameliorated and the disease turned its course. However, these results have not yet been published in peer-reviewed journals and therefore not yet validated in any forum in humans. Also the drug itself is not yet approved by US or European authorities.

Debate between physicians and the parents: should Baby Charlie be treated with nucleoside bypass therapy?

Recent headlines in British and international media, such as Guardian, BBC, Washington Post, New York Times, only to mention a few, have featured the tragic story of the baby Charlie Gard, his devastating terminal-stage disease, and his parents’ fight to get experimental nucleotide bypass therapy for their child. The family was desperate to have Charlie treated — who would not, for one’s own child. The story is heartbreaking and receiving increasing attention.

After the Pope commented that he is happy to offer his help, the media-coverage exploded. Also President Trump was offering Charlie help in the US, and some Republican senators are arranging a bill to offer citizenship for the whole family. The parents raised through internet over 1.6M pounds to transfer their baby to US for treament. In Rio de Janeiro, the statue of Christ was decorated with blue light for Charlie; a petition has been signed by almost 400.000 people to support his treatment, and many give their support through #IAmCharlieGard. Transfer of the baby to Vatican hospital — not known of their expertise on mitochondrial diseases — was discussed but denied by Italian authorities. The attention has been overwhelming, probably one of its kind in the history of rare diseases, and certainly among mitochondrial diseases.

However, it has been surprisingly little emphasized that Britain is a leader in developing therapies for mitochondrial diseases. The hospital and physicians involved in Baby Charlie’s treatment have excellent expertise in mitochondrial diseases, and actively using new therapeutic tools. Why are they not supportive for his therapy? Why was the court rule opposing Charlie’s treatment? The unfortunate fact is that Charlie’s disease is the most severe kind of MDS, causing gradual failure of all organs, including the brain. It is not the muscle-specific MDS, for which the nucleoside bypass therapy has been tested in mice and also in some patients. No research or experience of the therapy effect exists of Charlie’s disease type.

The expert doctors considered the therapy, but judged that his brain was damaged so badly that cure was beyond hope, even usingi experimental therapies. Based on available knowledge, the ethical boards and court all stated that the treatment may only extend the suffering of the child who already is in mechanic respiratory support, in critical condition.

Is there a point of no return considering treatability of a metabolic disease? Can brain damage be fixed?

Most of the mitochondrial disorders can be treated for their symptoms but not for the cause, and curative treatments do not exist. However, recent knowledge from other metabolic brain diseases may give some directions considering treatability of early infantile brain diseases. Mutations in B-vitamin transporters, such as folate and thiamine, cause severe, sometimes rapidly progressive infantile brain disorders. If high concentration folate / thiamine supplementation is given to patients, who already have developed a full-blown epileptic brain disease, the epilepsy may become less severe, but the brain damage exists. However, if the vitamin supplementation is initiated early-stage, the disease may be completely prevented. The take home lesson from this is the following: the existing brain damage cannot be fixed, but it is possible to prevent or stall progression of disease with early intervention. The idea behind nucleotide bypass therapy is the same: to give large amounts of the lacking substance. In the multiorgan MDS, such as the disase of Baby Charlie, early-stage treatment with large amounts of nucletides given to all tissues, could be useful. No knowledge exists of nucleotide access from blood to brain, as the research is still ongoing. The treatment might require intrathecal therapy (given to cerebrospinal fluid) for which compounds are not even available. In Charlie’s current state, the therapy might stall progression of the disease in muscle and heart, but not the brain. Therefore such therapy is not real therapy, but likely to extend the suffering. This is the main statement, to my opinion, against the therapy for a hopelessly sick child.

Ethical questions

If scientific evidence does not exist to support a treatment in a disease, should it be given based on educated guess? If there the therapy might stabilize only some tissues, should the treatment be given? Is stabilization good enough? What is considered to be a therapy success? Life extension, when unconcious, connected to mechanical respiratory support? It is also possible that the disease is acutely worsened by the therapy. Is it possible that already existing severe brain damage is cured? Will the empty spaces that lack functioning neurons repaired? No such cases are known in medicine to date from any field.

Many parents of children with uncurable diseases have had to make the hardest-of-all decisions: not to continue active treatment for their child. No-one should be in that situation, but if it happens, whose judgement can they base their decision on, if not their doctors’?

Future: there is hope

The current results concerning the nucleoside bypass therapy were only possible because of highest quality, careful basic research, decades of experience and work. Molecular knowledge is expanding of the devastating mitochondrial disorders, and current tools and understanding are raising hopes for therapies for some. I’m convinced that by developing basic research, and taking the results to treat early-stage diseases, we will be able to improve considerably the quality of life of some children with mitochondrial disorders, perhaps even cure.

For muscle-specific MDS the field is waiting for the publication of the preliminary promising results from Spain and USA. If verified to be useful, we want to be quick to start such therapy immediately when the diagnosis is done. As soon as possible.

Anu Suomalainen Wartiovaara

Written by

Academy Professor, MD PhD, @helsinkiuni @AWartiovaara. Research focus: Molecular basis and therapy for mitochondrial and metabolic diseases.

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