Nucleoside Bypass Therapy & Mitochondrial DNA Depletion Syndromes
What is Mitochondrial DNA Depletion Syndrome?
Mitochondria contain their own DNA, known as mitochondrial DNA (mtDNA), which is vital for mitochondria to produce energy. It is important that this mtDNA is correctly maintained to allow the mitochondria to function. Problems with mtDNA maintenance can reduce the amount and quality of the mtDNA which, in turn, can lead to impaired energy production. This can cause a particular type of Mitochondrial Disease known as Mitochondrial DNA Depletion Syndrome.
What are the causes?
Mitochondrial DNA Depletion Syndromes are caused by genetic errors (mutations) in genes found within the nuclear DNA. These mutations affect genes that have an essential role in the replication and maintenance of mtDNA and those commonly associated with disease include POLG1, TK2 and RRM2B.
What are the clinical features?
Mitochondrial DNA Depletion Syndromes are associated with many clinical features, some of which can be severe and often fatal in childhood. This can depend on the particular gene that is affected. In some cases, the main clinical feature is progressive muscle weakness, which can make breathing difficult and can lead to respiratory failure. Other parts of the body can also be affected, including the brain, liver, kidney and gastrointestinal tract.
How many people does it affect?
Mitochondrial DNA Depletion Syndromes are extremely rare. For example, there are thought to be <100 cases of Mitochondrial DNA Depletion Syndrome associated with the TK2 mutation throughout the world. The number is even less for Mitochondrial DNA Depletion Syndrome associated with the RRM2B mutation.
Who does it affect?
Mitochondrial DNA Depletion Syndromes can affect both children and adults. The early-onset form affecting infants and children is most severe and often fatal in early life. The late-onset form that affects adults is less severe and disease progression is often slower.
Is there a cure?
Unfortunately there are no cures at present for Mitochondrial Diseases, including Mitochondrial DNA Depletion Syndromes.
Are there any treatments?
Treatment usually focuses on managing the symptoms and providing supportive care. There is an experimental treatment, however, that may benefit some patients with Mitochondrial DNA Depletion Syndrome. This is known as nucleoside bypass therapy.
What is nucleoside bypass therapy?
There are four chemical ‘building blocks’ needed to maintain mtDNA, collectively known as deoxynucleoside triphosphates (dNTPs). If the body is unable to produce these dNTPs due to a mutation in one of the many genes that are needed to make them, this can result in Mitochondrial DNA Depletion Syndrome. It may be possible to ‘bypass’ this shortage of dNTPs by providing deoxynucleosides, or similar building blocks known as deoxynucleotides, to some patients with Mitochondrial DNA Depletion Syndrome as an oral medication. This may restore the supply of dNTPs required for mtDNA maintenance, which could improve some of the clinical symptoms associated with the condition.
What preclinical research has been done?
Mouse models of Mitochondrial DNA Depletion Syndrome have shown that nucleoside bypass therapy can delay the onset of disease, reduce the severity of symptoms and extend the lifespan of mice with a TK2 mutation when compared to untreated mice. It can also restore the amount of mtDNA, leading to improved energy production by the mitochondria.
Similar findings have been described in cultured cells taken from patients with TK2 mutations causing Mitochondrial DNA Depletion Syndrome. It has been shown that supplementing these cells with nucleosides can prevent a reduction in the amount of mtDNA.
Is nucleoside bypass therapy being used?
Based on preclinical research, nucleoside bypass therapy is being used for a small number of patients in both Europe and America on compassionate grounds. Importantly, all of these patients have Mitochondrial DNA Depletion Syndrome associated with the TK2 mutation, which mainly affects muscle.
Although initial effects of the therapy appear to be encouraging, the results have not been published or evaluated by other experts working in the field (known as ‘peer-review’).
Have there been any clinical trials?
There have been no clinical trials of nucleoside bypass therapy for Mitochondrial DNA Depletion Syndromes.
The gold standard clinical trial is a double-blind randomised placebo controlled trial. This involves randomly dividing participants into two groups, with one group receiving the active drug and the other receiving a dummy treatment (placebo). Neither the researchers nor the participants know who has received the active drug or placebo until the end of the trial, at which point the results from both groups can be compared.
The encouraging preliminary results in patients already receiving nucleoside bypass therapy would make it practically and ethically difficult to run a randomised double-blind placebo controlled trial, especially in severely affected children. As there is no standard or alternative treatment available with which to compare nucleoside bypass therapy, the best option is to compare the outcomes for patients receiving treatment with those who did not receive this treatment in the past.
Another obstacle in running a clinical trial is that Mitochondrial DNA Depletion Syndromes are very rare and show a spectrum of severity, making it difficult to recruit sufficient numbers of patients. International collaboration on such clinical trials is a necessity and the Lily Foundation are supporting the development of an international patient registry to help achieve this goal.
Will nucleoside bypass therapy be suitable for all Mitochondrial DNA Depletion Syndromes?
It is unclear at this stage whether nucleoside bypass therapy could be used for Mitochondrial DNA Depletion Syndromes caused by mutations in genes other than TK2. Further preclinical studies are required to determine whether the therapy can be used to treat all Mitochondrial DNA Depletion Syndromes.