Nicotinamide Riboside and Mitochondrial Biogenesis
Condition: Mitochondrial Diseases; Mitochondrial Myopathies; Progressive External Ophthalmoplegia; Progressive Ophthalmoplegia; Progressive; Ophthalmoplegia, External; Mitochondria DNA Deletion; MELAS
MeSH terms: Mitochondrial Myopathies; Ophthalmoplegia, Chronic Progressive External; Ophthalmoplegia; Mitochondrial Diseases
Study type: Interventional

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
    

Intervention name(s): Nicotinamide Riboside
Intervention type(s): Dietary Supplement
Intervention description(s): Nicotinamide Riboside is a member of the Vitamin B family which acts as a precursor to NAD+, an enzyme involved in energy production.
Other intervention name(s): Niagen; Nicotinamide Riboside Chloride
Intervention MeSH terms: Niacinamide; Niacin; Nicotinic Acids
Intervention model: Single Group Assignment
Intervention model description: Experimental medicine study (open label)
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Mitochondria; Mitochondrial disease; Nicotinamide Riboside; Niagen; PEO; Single deletion; mtDNA deletion; MELAS; m.3243A>G