MELAS, Mitochondria DNA Deletion, Mitochondrial Diseases, Mitochondrial Myopathies, Progressive External Ophthalmoplegia, Progressive Ophthalmoplegia, Progressive; Ophthalmoplegia, External
Conditions
Keywords
Mitochondria, Mitochondrial disease, Nicotinamide Riboside, Niagen, PEO, Single deletion, mtDNA deletion, MELAS, m.3243A>G
Brief summary
Mitochondria are important parts of the cell that are responsible for producing energy. The amount of energy they produce depends on how much energy the body needs to function and this energy production can be severely impaired in people with mitochondrial disease. Symptoms of mitochondrial disease vary widely but usually involve the brain, nerves and muscles, as these are tissues that need a lot of energy. Mitochondrial disorders affect 1 in 5000 of the UK population and there is currently no cure. Some scientists think that increasing the number of mitochondria in the body (mitochondrial biogenesis) might be an effective treatment for the symptoms of mitochondrial disease. Studies carried out in mice have shown that a type of B-vitamin called Nicotinamide Riboside (NR) is able to increase the number of mitochondria, leading to increased energy and a reduction in the symptoms of mitochondrial disease. The aim of this study is to investigate if the same B vitamin, Nicotinamide Riboside, can increase energy production and reduce symptoms in humans with mitochondrial disease. The study will consist of two parts: Part 1: Participants will be given a single oral dose of Nicotinamide Riboside and the levels of NR in their bloodstream will be measured at regular intervals. This will involve a single overnight stay and simple blood tests. Part 2: This requires 6 separate visits from each participant. Each participant will undergo a series of standard tests including a muscle biopsy and an MRI scan, then they will take a course of Nicotinamide Riboside (twice daily for 4 weeks). After 4 weeks of treatment, the participants will undergo the same tests again to see if there have been any changes in response to the treatment.
Detailed description
Mitochondria are the primary source of energy within the cell, in the form of adenosine triphosphate (ATP). Mitochondrial ATP production is tightly regulated according to the energy requirements of the cell, but little is known about the underlying control mechanisms. This is important for the understanding of the biology of cell energetics and also relevant for patients with rare mitochondrial diseases where it has been proposed that inducing mitochondrial proliferation (biogenesis) might be an effective treatment. However, before embarking on therapeutic studies, it is essential to develop our understanding of the homeostatic mechanisms. Patients with mitochondrial diseases show an enhanced capacity for mitochondrial proliferation, and therefore provide an ideal platform to study mitochondrial homeostasis in vivo in man. The aim of this study, therefore, is to investigate the homeostatic mechanisms in this group of individuals because we are most likely to see an effect in this context. Nicotinamide riboside (NR), a NAD+ natural precursor, boosts the PGC1α-dependent mitochondrial biogenesis pathway, leading to increased transcription of genes of the oxidative phosphorylation and improved motor performance of myopathic mice. This study is an open-label experimental medicine study using NR with the primary aim of determining whether there is mechanistic link between mitochondrial biogenesis and physiological function in humans with a similar mitochondrial disease. This project consists of two studies, carried out in series. Both will investigate patients with a clinical and genetic diagnosis of: i. Progressive external ophthalmoplegia (PEO) plus exercise intolerance/fatigue, caused by a single deletion of mitochondrial DNA or ii. Mitochondrial disease caused by the m.3243A\>G mutation in mitochondrial DNA Study 1: a 24 hour study before the experimental intervention, to confirm bioavailability of NR at a dosage within the range of a published study. Patients (n=5) will be invited to the CRF for an overnight stay. If applicable, a urinary pregnancy test will be carried out before any study procedures commence. A baseline blood sample will be taken before administration of the supplement. Oral NR will be administered at a dosage of 10mg/kg -, and blood samples will be drawn at 30 mins,1, 2, 6, 12 and 24 hours post administration. These samples will be used for measurement of NR/NAD+ levels in blood at the relevant time points and ensure these are at expected levels before proceeding to experimental intervention. Study 2: a 4-week study to determine whether NR induces mitochondrial biogenesis and affects mitochondrial function in patients with mitochondrial disease. Patients (n=10) will undergo measurements of mitochondrial biogenesis and physiological activities. Oral NR will be administered at a dosage of 10mg/kg b.i.d, (taken twice daily, after food) and patients will be asked to return weekly for standard observations and to provide a blood sample. After 4 weeks of NR administration, patients will return for a repeat measure of the mitochondrial biogenesis parameters and physiological activities
Interventions
DIETARY_SUPPLEMENTNicotinamide Riboside
Nicotinamide Riboside is a member of the Vitamin B family which acts as a precursor to NAD+, an enzyme involved in energy production.
Sponsors
University of Cambridge
Medical Research Council Mitochondrial Biology Unit
Cambridge University Hospitals NHS Foundation Trust
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Experimental medicine study (open label)
Intervention model description
Experimental medicine study (open label)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Clinical and genetic diagnosis of: * Progressive external ophthalmoplegia (PEO), caused by a single deletion of mitochondrial DNA * or * Mitochondrial disease caused by the m.3243A\>G or A\>T mutation in mitochondrial DNA * Age 18-70 years * Women of child-bearing age only if they are not pregnant or breast feeding at the inclusion into the study and agree not to become pregnant during the study. Female participants will undergo a pregnancy test before study commencement. * Signed informed patient consent
Exclusion criteria
* Clinically significant liver disease (e.g., cirrhosis or a history of hepatitis) * Presence of significant other neurological disorders (such as multiple sclerosis, Parkinson's disease) or major co-morbidities (such as definite cognitive impairment, psychiatric disease, heart or lung failure, orthopaedic or rheumatological disorders) * Females who are at risk of pregnancy (i.e., not using regular contraception), who are pregnant, lactating or planning pregnancy * Females taking the combined oral contraceptive pill (as oestrogens can induce mitochondrial biogenesis and interfere with study results) * For MRI - medical contraindication e.g., pacemaker, deep brain stimulator, aneurysm clip or significant claustrophobia * For biopsy - varicose veins overlying biopsy site, clinically significant lower limb oedema, active lower limb infection, use of anticoagulants or antiplatelet agents that cannot be discontinued, known bleeding diathesis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mitochondrial biogenesis - mitochondrial DNA quantification | 4 weeks | Change from baseline in the amount of mitochondrial DNA at the start and end of the 4 weeks of NR treatment (mtDNA quantification) |
| Safety - blood pressure | Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose | Change from baseline in patient blood pressure (mmHg, measurement at 0, 0.5, 1, 2, 6, 12 and 24 hours) |
| Safety - pulse | Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose | Change from baseline in patient pulse (bpm, measurement at 0, 0.5, 1, 2, 6, 12 and 24 hours) |
| Mitochondrial biogenesis - Magnetic Resonance Imaging | 4 weeks | Change in in vivo measurement of mitochondrial function at the start and end of the 4 weeks of NR treatment (31P-MRS measurement of mitochondrial function - Phosphocreatine replenishment after exercise) |
| Mitochondrial biogenesis - Respiratory Chain Enzyme Analysis | 4 weeks | Change from baseline in mitochondrial function at the start and end of the 4 weeks of NR treatment (Respiratory chain enzyme analysis) |
| Bioavailability | Pharmacokinetic measure - 0, 0.5, 1, 2, 6, 12 and 24 hours post-dose | Change in baseline levels of Nicotinamide Riboside detectable in the bloodstream of participants after a standard oral dose of the supplement (at 0, 0.5, 1, 2, 6, 12 and 24 hours) |
| Safety - Incidence of treatment related adverse events | 24 hours | Observation over 24 hours after Nicotinamide Riboside administration. Recording of any adverse events or reactions |
| Safety - change in blood analytes | 24 hours | Change from baseline in safety blood analyte levels - CK, Creatinine, Alanine Transaminase, Aspartate Transaminase (Units U/L) |
| Safety - temperature | Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose | Change from baseline in patient temperature (degrees celsius, measurement at 0, 0.5, 1, 2, 6, 12 and 24 hours) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Impact on mitochondrial disease symptoms - 6-minute walk | 4 weeks | Participants will be asked to complete the 6 minute walk test before and after treatment. The distance they can walk in 6 minutes will be measured in metres. |
| Impact on mitochondrial disease symptoms - Quality of life (SF36 - qualitative) | 4 weeks | Participants will be asked to complete the SF36 (Short Form 36) Quality of life questionnaire before and after treatment. This is a standard health survey used routinely in clinical practice. |
| Impact on mitochondrial disease symptoms - Timed get-up-and-go. | 4 weeks | Participants will be asked to complete the Timed up and go test before and after treatment. The time taken to get up from sitting to standing will be measured in seconds. |
| Impact on mitochondrial disease symptoms - Dynamometric measure of muscle strength | 4 weeks | Participants will be asked to complete the dynamometric measure of muscle strength test, using a hand held dynamometer, before and after treatment. Force measured in kg. |
Countries
United Kingdom
Outcome results
None listed