Fighting Mitochondrial Disease.
Fighting For Hope!
Supporting medical research into mitochondrial disease is a fundamental aspect of our work, not only because it could potentially lead to a cure but also because it helps to improve lives now. Lily-funded research projects have already resulted in faster, less invasive patient diagnosis and helped families affected by mitochondrial illness to have healthy babies. Several promising avenues for new treatments are also currently being explored.
Mitochondrial disease can result in restricted mobility including ptosis, an inability to fully open the eye. Mitochondrial function is improved by red light and there is evidence that this improves ptosis. This pilot study will use red light and measure its ability to improve eye opening in children with mitochondrial disease. Families will be given a specially designed, safe-to-use torch to shine a red light through the closed eyelid for 3 minutes a day and will visit the hospital for assessments throughout the duration of the study. The results will provide important data about whether this treatment helps to strengthen the muscles in the eyelid and help make it easier to open the eyes. (2023-2025)
To find out more about this study, including how to take part, please click here
Mutations in mitochondrial genes that mainly affect the muscles are known as Primary Mitochondrial Myopathies (PMMs), and can cause symptoms including exercise intolerance, muscle pain (myalgia), fatigue and muscle wasting. A significant obstacle in diagnosing and monitoring progression of PMMs is the ability to accurately assess muscle involvement. Current methods, such as MRI, have been unable to generate robust data, meaning that improved methods to capture changes in muscle are needed. In addition, due to their severity and impact on patient's lives, muscle symptoms are often the target of drug trials - however, the sensitivity of current measures is impacting trial outcomes because they are unable to capture modest drug effects on muscle throughout a trial's lifetime. This study will use a special MRI technique to test whether measuring the efficiency of oxygen utilisation by the muscle tissue (the “oxygen extraction fraction”), could be a valid method to identify muscle changes even at the early stages of disease. (2023-2025)
Mitochondrial DNA depletion and deletions syndromes (MDDSs) are characterised by low levels of mitochondrial DNA (mtDNA) and the accumulation of damaged mtDNA molecules in affected tissues. Often the mtDNA abnormalities are the results of a shortage or imbalance of the building blocks of the DNA, the nucleotides, hence supplementation of these holds promise as a treatment. This new study will focus on MDDS caused by mutations in the MPV17 gene, which manifests as severe liver disease and neuro-muscular damage. Researchers will use a MPV17 deficient mouse that displays several features of the human disease to investigate whether nucleoside supplementation is effective long-term at restoring mtDNA numbers and preventing the accumulation of damaged molecules in liver and muscle and whether the treatment prevents and reverses the loss of mitochondrial and organ function. If successful, this could lead to trials in human patients with MPV17 mutations, as well as potentially also being extended to treat other mtDNA disorders in the future. (2022-2023)
Hearing loss is a common problem related to mitochondrial disease, affecting up to 1-in-8 patients. Problems with hearing can have a major impact on communication, social participation, and well-being. The standard treatment for mild to-moderate hearing loss for patients with mitochondrial disease is hearing aids; however, these are often ineffective as they make sounds louder, but not clearer. This can lead to patients feeling dissatisfied with traditional hearing aids, and they may choose not to wear them. The EMERALD study will test a new type of technology, called a remote microphone Assistive Listening Device (ALD) which can enhance the use of traditional hearing aids by making it easier to understand speech, especially where there is a lot of background noise. The study will test whether using an ALD can improve hearing and communication and improve well-being and social participation. The study will also assess levels of patient satisfaction and whether the new device is well-tolerated by patients. (2022-2024)
Mitochondrial diseases can affect any part of the body but tend to affect organs that require a lot of energy to function. Patients with mitochondrial disease caused by the genetic mutation ‘m.4300A>G’ often develop serious problems with their heart muscle (cardiomyopathy), which can be fatal unless they have a heart transplant. Previous studies have shown that increasing the rate of mitochondrial recycling through a process called mitophagy could potentially benefit cells with mitochondrial DNA mutations. This study aims to test whether a drug known to increase mitophagy could benefit this group of patients by reducing the risk of developing cardiomyopathy. This drug is already widely used for another medical condition so if successful, could be a candidate for fast track to mitochondrial patients and has the potential to treat individuals before symptoms present which would greatly reduce disease burden. The study will also test whether upregulating mitophagy could be beneficial in other types of mitochondrial disease thus broadening the scope of the research. (2021-2022)
Epilepsy is common in children and adults with mitochondrial disease. Seizures in these patients may not respond to multiple anti-epileptic drugs and can lead to serious neurological consequences with poor outcomes. Transcranial direct current stimulation is a treatment that delivers a very low current and has been shown to calm seizure activity. The technique has been used successfully in a small number of patients under special circumstances. This new study, called TRANSFORM, aims to establish whether this treatment improves seizure control enough to be offered as a new treatment option for a larger number of patients with mitochondrial disease and epilepsy. (2021-2024)
Transform research study now open to people with mitochondrial epilepsy
The study is now open to people with mitochondrial disease and drug-resistant focal epilepsy who show anatomically relevant changes in the brain (neuroimaging or EEG).
If you are interested in finding out more, or would like to participate, please click here or contact us:
Prof Robert McFarland at +44 191 2825225, Dr Albert Lim via [email protected] or Katrin Bangel via
Genetic mistakes in a gene called ‘POLG’ are associated with mitochondrial diseases in which people typically have a reduced amount or quality of mitochondrial DNA (mtDNA). This depletion of mtDNA can lead to impaired energy generation in affected tissues and can cause a spectrum of POLG-related mitochondrial disorders which present with a wide range of debilitating symptoms. The aim of the project is to perform an extensive review of the published literature to provide a deeper understanding of particular aspects of POLG-related disease. This will lead to benefits for patients, including the identification of potential therapies and the generation of consensus guidelines for the clinical management of POLG disease. (2020-2021)
Patient experiences of any condition are vital for medical research and allow researchers to fully understand the impact of the disease. The RUDY platform is an established, secure medical database which has UK research ethics approval to collect patient data for research purposes. This project aims to build a mitochondrial disease profile into the existing platform to allow mitochondrial patients to contribute information about their disease experience, lifestyle and clinical history. This platform has proven success in other disease areas and allows more patients to participate in research by removing factors such as travel costs, health and mobility which often restrict participation. This project is a collaboration of all 3 specialist mitochondrial centres in the UK (London, Newcastle and Oxford) and all UK mitochondrial patients will be able to register and contribute to this research which will help improve the understanding of mitochondrial disease and ultimately lead to better treatments for patients. (2020-2022)
Involvement of the brain in mitochondrial disease is common. As well as seizures and stroke like episodes, neurological consequences can often include neuropsychiatric symptoms such as anxiety, agitation, emotional dysregulation, depression and/or altered sensory perception. There has been no systematic study of these clinical aspects of mitochondrial disease, which are often missed and can be greatly disabling and distressing for patients. The study aims to collect detailed information on neuropsychiatric symptoms and brain imaging biomarkers in adult patients with mitochondrial disease which will help guide better clinical care. This information will also be invaluable for future clinical trials of novel drugs aimed at restoring mitochondrial function in the brain. (2021-2023)
The Lily Foundation is providing additional funding to support a pilot study funded by Muscular Dystrophy UK to test a chemical that could improve muscle weakness in some patients with mitochondrial disease caused by mutations in the mitochondrial DNA (mtDNA). Most patients with mtDNA mutations have a mixture of both normal and mutated mtDNA in the cells of their body, and it is only when the amount of mutated mtDNA exceeds a certain level that disease symptoms appear. A chemical has been identified that is able to promote normal mtDNA but not mutated mtDNA in cells grown in the laboratory, leading to an increase in the amount of healthy mitochondria. This small-scale study will test the chemical in people with the most common mtDNA mutation (m.3243A>G) to find out if it has the same effect in the body and can increase the amount of healthy mitochondria in muscle. The study will provide important information for future clinical trials, such as optimal dosing and safety. The chemical could be an effective treatment for people with the m.3243A>G mutation but could also benefit those with other mitochondrial diseases caused by mutations in the mtDNA. (2019-2021)
The study aims to generate new zebrafish models of mitochondrial DNA depletion syndrome (MDDS), a mitochondrial disease characterised by low levels of mitochondrial DNA (mtDNA) in affected tissues. The purpose of the study is to use the zebrafish models to test potential therapeutic options for MDDS. One such technique is called nucleoside supplementation, which aims to prevent a reduction in the amount of mtDNA by providing the 'building blocks' needed for mtDNA maintenance. This will include testing chemically modified building blocks that the researchers hope will have better bioavailability, and should be more easily absorbed by the body. There is currently no cure for MDDS, and this research could be an important step in developing a treatment that improves some of the clinical symptoms associated with the condition. (2019-2022)
Balance disturbance, including dizziness and unsteadiness, is common in people with mitochondrial disease. The study will support the development of assessment guidelines that help understand the cause of balance disturbance, which will allow for earlier identification and improved management of these disabling symptoms. This will benefit patients by helping to reduce falls, improving safety and enhancing quality of life through access to targeted physiotherapy. (2019-2022)
The study aims to develop a gene therapy technique to remove faulty mitochondrial DNA (mtDNA) in an animal model of mitochondrial disease. The technique makes use of an engineered enzyme that is directed to the faulty mtDNA, where it acts like a pair of scissors to cut the mtDNA. This causes the faulty mtDNA to be removed from the cell, allowing the healthy mtDNA to take its place. The researchers have shown previously that this works in heart tissue in a mouse model of mitochondrial disease, so the next step is to test it in other tissues often affected in mitochondrial disease, including brain and muscle. It is proposed that removing faulty mtDNA in this way could lead to an improvement in the symptoms seen in patients with mitochondrial disease, and it is hoped that the study will provide the vital pre-clinical data on efficacy and safety required to take the next steps towards using this strategy to treat patients. (2019-2023)
Clinical trials for any kind of mitochondrial disease can be greatly improved by ensuring that patients are ‘trial ready’. Part of this process involves studying the clinical features of patients in detail, which allows the development of meaningful outcome measures that can be used to determine if a treatment is having a clinical benefit. The Lily Foundation is funding a study that aims to collect this information for patients with mitochondrial disease caused by a genetic fault in the gene RRM2B. This research project also aims to develop new drugs that could potentially be used to treat patients with this type of mitochondrial disease and to test these drugs in cell models derived from patient skin cells. (2018-2019)
Increased heart size is a common symptom in mitochondrial disease that can lead to heart failure and even death. Previous research has identified a specific set of chemical reactions (known as a metabolic pathway) that may be more active in patients with mitochondrial disease. The Lily Foundation is funding research to test a drug that could reduce the activity of this pathway as a way to prevent or slow down the increase in heart size using a mouse model of mitochondrial disease. This could be of huge benefit to many patients with mitochondrial disease. (2018-2019)
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare mitochondrial condition that is caused by a genetic fault in a gene that codes for an enzyme which removes certain biological molecules from the body. When the enzyme doesn’t work properly, the molecules begin to build up which causes damage to the mitochondria. A team based at University of London are due to begin a clinical trial to test a therapy for MNGIE where the missing enzyme is added to the patient’s own red blood cells, resulting in the unwanted biological molecules being removed from the blood. The Lily Foundation is funding research to assess potential biomarkers found in blood that can be used in this clinical trial to measure the clinical benefit of this therapy in patients with MNGIE. (2018-2020)
The cells of our body have a protective mechanism that can remove and recycle different parts of the cell if they are no longer needed or become damaged. When this refers specifically to the removal of mitochondria, the process is known as ‘mitophagy’. The rate of mitophagy appears to be higher in a number of mitochondrial diseases and if these mitochondria are not being replaced within the cell, or the cell is using too many of the building blocks to try and replace the mitochondrial DNA, this could lead to mitochondrial DNA depletion syndrome.
The Lily Foundation is funding a study that aims to investigate the rate of mitophagy in skin cells taken from patients with MDDS. The study will test nucleoside bypass therapy and other re-purposed compounds that could reduce the rate of mitophagy, which could potentially benefit patients with any type of mitochondrial DNA depletion syndrome. (2018-2020).
Nicotinamide Riboside (NR) is a form of vitamin B3 that has been shown to increase the number of healthy mitochondria in animal models of Mitochondrial Disease. This could benefit patients by reducing some of the symptoms of Mitochondrial Disease. In its current form, only low levels of NR reach the bloodstream after a tablet is taken. The Lily Foundation is funding research to improve the uptake of NR into the bloodstream and maximise the positive effects on mitochondria. If successful this could lead to clinical trials of NR as a potential treatment for Mitochondrial Disease. (2018-2019)
Mitochondrial Diseases are caused by mutations in the genetic code found within our cells. Some of these mutations change the genetic code in such a way that the cell is unable to produce the protein it needs for mitochondria to work. A certain type of drug known as translational read-through inducing drugs (TRIDs) may enable the gene mutation to be 'overlooked' so that protein production in cells could still occur. The Lily Foundation is funding research to test the effectiveness of TRIDs on cells from patients with Mitochondrial Disease caused by various gene mutations. These drugs could potentially be used to treat a wide range of Mitochondrial Diseases and benefit many patients. (2017-2019)
Symptoms involving the gut are common in patients with Mitochondrial Disease. Research has shown that some of these symptoms can be alleviated by limiting the amount of foods that are not easily digested in the gut. This 'low residue diet' results in less undigested food remaining in the gut, leading to easier passage of stools through the bowel and fewer and smaller bowel movements. The Lily Foundation is funding research which aims to provide more information about the effects of a low residue diet on Mitochondrial Disease patients with gut related symptoms. (2017-2018)
Lily Exome Sequencing is a groundbreaking diagnostic technique whereby 1000's of genes can be analysed simultaneously, instead of one at a time as was previously the case. The time taken to locate the faulty genes that cause mitochondrial disease has been dramatically reduced, resulting in faster and more accurate diagnosis. Once families know the genetic cause of their mitochondrial disease, they are able to make important life decisions in relation to managing their condition and family planning. Many healthy children, free from mitochondrial disease, have been born thanks to this advance.
Defects in nuclear DNA account for approximately 75-80% of paediatric Mitochondrial Disease, but it is estimated that only a tiny proportion of these cases actually have a confirmed genetic diagnosis.
There are believed to be over 1000 nuclear genes involved in mitochondrial function, but to date only around 300 of these have been linked to disease, making genetic diagnosis of nuclear DNA disease a huge challenge.
The NHS genetic testing service currently only screens for about 4% of these known genes which leaves a very high proportion of families with no answers. Genetic diagnosis can be invaluable when assessing risk to other family members, for future family planning and in some cases, it can even help direct treatment.
Exome sequencing is a technique which can look at 1000's of genes at the same time, and is much more efficient than standard single gene testing. Unfortunately there is currently no NHS provision for exome sequencing.
In 2012, Lily and the team at Guy's & St Thomas' set about trying to change this. They planned and developed a detailed genetic testing pathway and with the support of Newcastle University they started recruiting families in early 2014.
The aim of our Lily exome sequencing project would be to sequence 100 patients with nuclear mitochondrial defects, giving families a genetic diagnosis for their Mitochondrial Disease and hopefully, in the process, discover new disease causing genes to help improve the understanding of this condition.
This ambitious project would accept samples from all over the country via the 3 major centres of excellence in Mitochondrial Disease (Newcastle, Oxford and London).
To date we have screened 202 families and provided definite, or highly likely answers in 73% of these cases.
Before our study, families often had to wait years to get a genetic diagnosis for their child, and even then, the success rate was low, with maybe only 20% receiving the genetic diagnosis they had hoped for.
Unfortunately, a minority of our families still do not receive a genetic diagnosis from initial screening, so further investigation work is required. Lily funds 2 specialist mitochondrial disease researchers at Newcastle to undertake follow up work on these cases, to ensure all our families (even those with very rare forms of disease) have the best opportunity to get a genetic diagnosis.
Lily funding has already identified 34 novel mutations linked to mitochondrial function which were not previously known to cause disease, so our work is greatly advancing the understanding of Mitochondrial Disease, as well as helping give answers to individual families.
Our project is the first country wide collaboration of its kind for Mitochondrial Disease diagnostics in the UK, and we will continue to fund this valuable testing for families, until an equivalent NHS service is in place.
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