Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
| Status: | Recruiting |
|---|---|
| Conditions: | Cancer, Cancer, Neurology |
| Therapuetic Areas: | Neurology, Oncology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 3/15/2019 |
| Start Date: | January 25, 2019 |
| End Date: | July 12, 2021 |
| Contact: | Rebecca D Huffstutler, C.R.N.P. |
| Email: | rebecca.huffstutler@nih.gov |
| Phone: | (301) 594-1281 |
Exploratory Study of Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome
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The participant will be withdrawn from the study if they become pregnant.
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.
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 patient s 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 patient s 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.
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 patient s 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 patient s 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.
- INCLUSION CRITERIA:
- At least 18-years of age and able to give informed consent
- Have delayed PCr recovery time constant >45 sec by 31P-MRS testing and a history of
fatigue symptoms
- Ability to undergo study procedures, including scheduled visits, blood draws and
skeletal muscle exercise NMR spectroscopy
- Have Li-Fraumeni syndrome and confirmed TP53 mutation by genetic testing
- Committed to using reliable contraception which may include abstinence during study
participation
- Female participants of child-bearing ability and potential willing to commit to
reliable contraception while participating in the study
EXCLUSION CRITERIA:
- Current systemic treatment for cancer
- Unable to perform required study visits or procedures
- MRI incompatible hardware
- Pregnant or breastfeeding women
- History of intolerance to NR precursor compounds, including niacin or nicotinamide
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
301-496-2563
Phone: 800-411-1222
National Institutes of Health Clinical Center The National Institutes of Health (NIH) Clinical Center in...
Click here to add this to my saved trials
