Nicotinamide Riboside and Mitochondrial Biogenesis
Palabras clave
Abstracto
Descripción
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
fechas
| Verificado por última vez: | 06/30/2019 |
| Primero enviado: | 01/22/2018 |
| Inscripción estimada enviada: | 02/12/2018 |
| Publicado por primera vez: | 02/13/2018 |
| Última actualización enviada: | 07/03/2019 |
| Última actualización publicada: | 07/07/2019 |
| Fecha de inicio real del estudio: | 12/07/2017 |
| Fecha estimada de finalización primaria: | 12/30/2019 |
| Fecha estimada de finalización del estudio: | 12/30/2019 |
Condición o enfermedad
Intervención / tratamiento
Dietary Supplement: Nicotinamide Riboside
Fase
Grupos de brazos
| Brazo | Intervención / tratamiento |
|---|---|
| Experimental: Nicotinamide Riboside This is an open-label experimental medicine study.
All subjects will receive the same dosage of the supplement Nicotinamide Riboside. | Dietary Supplement: Nicotinamide Riboside Nicotinamide Riboside is a member of the Vitamin B family which acts as a precursor to NAD+, an enzyme involved in energy production. |
Criterio de elegibilidad
| Edades elegibles para estudiar | 18 Years A 18 Years |
| Sexos elegibles para estudiar | All |
| Acepta voluntarios saludables | si |
| Criterios | Inclusion Criteria: Clinical and genetic diagnosis of: - Progressive external ophthalmoplegia (PEO) plus exercise intolerance/fatigue, caused by a single deletion of mitochondrial DNA - or - Mitochondrial disease caused by the m.3243A>G 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: - Pure PEO without exercise intolerance/fatigue - 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 |
Salir
Medidas de resultado primarias
1. Bioavailability [Pharmacokinetic measure - 0, 0.5, 1, 2, 6, 12 and 24 hours post-dose]
2. Safety - Incidence of treatment related adverse events [24 hours]
3. Safety - change in blood analytes [24 hours]
4. Safety - temperature [Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose]
5. Safety - blood pressure [Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose]
6. Safety - pulse [Change measures - 0, 1, 2, 3, 4, 6, 8, 24 hours post-dose]
7. Mitochondrial biogenesis - Magnetic Resonance Imaging [4 weeks]
8. Mitochondrial biogenesis - Respiratory Chain Enzyme Analysis [4 weeks]
9. Mitochondrial biogenesis - mitochondrial DNA quantification [4 weeks]
Medidas de resultado secundarias
1. Impact on mitochondrial disease symptoms - Dynamometric measure of muscle strength [4 weeks]
2. Impact on mitochondrial disease symptoms - 6-minute walk [4 weeks]
3. Impact on mitochondrial disease symptoms - Quality of life (SF36 - qualitative) [4 weeks]
4. Impact on mitochondrial disease symptoms - Timed get-up-and-go. [4 weeks]
