Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
Condition: Cancer; Skin Fibroblasts; Muscle Weakness
MeSH terms: Li-Fraumeni Syndrome; Muscle Weakness
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      Nicotinamide riboside (NR) is a vitamin B3 dietary supplement. It may help improve muscle
      function, that may in turn may improve a person s exercise capacity. Researchers want to
      study how skeletal muscle responds to NR in an individual who has Li-Fraumeni Syndrome and
      slow muscle energy recovery after exercise.

      Objective:

      To study how nicotinamide riboside affects skeletal muscle after exercise.

      Eligibility:

      One person at least 18 years old with Li-Fraumeni syndrome and a certain gene mutation

      Design:

      The participant will be screened with a medical history, physical exam, and blood and urine
      tests.

      The participant may also have a heart test.

      The participant will maintain their regular diet and supplements during the study.

      The participant will take the study drug as 1-4 tablets twice a day for 12 weeks. The
      participant may be contacted with reminders and questions about side effects.

      The participant will have 4-5 visits over 18-30 weeks. At visits, the participant will repeat
      screening tests. At some visits they will also have:

        -  Ultrasound of the heart with a wand placed on the chest.

        -  Test of oxygen used at rest and exercise, while wearing a face mask.

        -  Exercise test on a treadmill or bicycle with electrodes on the skin.

        -  Magnetic resonance spectroscopy. The participant will have no caffeine for 12 hours.
           Then they will lie in a machine for about 2 hours. Sometimes they will lie still.
           Sometimes they will be asked to move.

      Health questionnaire

      The participant may have a skin sample taken by needle.

      The participant will be withdrawn from the study if they become pregnant.
    

Detailed description: 
      We have previously reported that inherited mutations of TP53, which causes the premature
      cancer disorder Li-Fraumeni syndrome (LFS), can promote mitochondrial function both in
      patients and mouse models. In the course of our follow up studies, we encountered a LFS
      patient with a long-standing history of fatigue and muscle weakness of unclear etiology.
      Notably, we observed in vivo evidence of markedly decreased mitochondrial function in her leg
      skeletal muscle during exercise using noninvasive phosphorus-31 magnetic resonance
      spectroscopy (31P-MRS), a technique that has previously been used to study patients with
      primary mitochondrial disorders. The decrease in mitochondrial function was also confirmed by
      the patients skin fibroblasts in vitro using standard biochemical measurements.

      There is growing evidence that nicotinamide adenine dinucleotide (NAD+) homeostasis plays a
      significant role in maintaining the mitochondria through various mechanisms and that it is
      possible to improve mitochondrial function by dietary supplementation with the vitamin B3
      analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. Remarkably,
      we observed that culturing the LFS patients fibroblasts in medium containing NR rescued the
      severe deficit in mitochondrial respiration. While continuing our investigations into the
      molecular mechanism(s) underlying the mitochondrial dysfunction observed in this patient, the
      in vitro rescue of the respiratory deficiency by NR presents a unique opportunity to
      investigate whether it can also be observed in vivo using skeletal muscle 31P-MRS. We propose
      to explore the effect of NR, currently available as a dietary supplement, on in vivo
      mitochondrial function in this LFS patient.
    

Intervention name(s): Nicotinamide Riboside (NR)
Intervention type(s): Dietary Supplement
Intervention description(s): Niacin is a form of vitamin B3 and has been used to treat hypercholesterolemia for many years. There is growing evidence that nicotinamide adenine dinucleotide (NAD+ can maintain mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. We have observed that culturing the fibroblasts of a LFS patient with mitochondrial deficiency in medium containing NR rescues the defect in mitochondrial respiration.
Other intervention name(s): Niagen; Nicotinamide Riboside (NR)
Intervention MeSH terms: Niacinamide; Niacin; Nicotinic Acids
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Oxidative Phosphorylation Capacity; Increased Oxidative Metabolism; Regeneration of Phosphocreatine (PCr); Inherited Mutation of TP53 Tumor Suppressor Gene