Amazentis (AMZ) has identified the first ingredient that is able to stimulate mitophagy, namely AZ400, a natural product derived from food. AMZ has conducted several preclinical studies showing that AZ400 has a strong potential to improve muscle…
ID
Source
Brief title
Condition
- Other condition
- Musculoskeletal and connective tissue disorders NEC
Synonym
Health condition
mitochondriele dysfunctie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the level of mitophagy and autophagy in muscle biopsy tissue of
active healthy elderly subjects and sedentary pre-frail elderly subjects using
1) gene expression and 2) protein expression analysis for candidate genes
linked to mitophagy and autophagy biological process.
Secondary outcome
- PCr recovery time (in seconds) measured by 31P-MRS.
- Ratio of mtDNA to nuDNA measured by qPCR.
- Activity of citrate synthase and respiratory complexes measured by assay in
muscle tissue.
- mVO2 (in ml/min/100 ml) in muscle measured by NIRS.
- MitoPO2 (in mmHg) in the skin measured by PpIX-TSLT.
- Hand grip strength (in kg) measured by the Jamar dynamometer.
- Strength during maximum voluntary isometric contraction of the quadriceps (in
kg).
- Postural stability (in cm sway) measured by body sway.
- Ability to maintain standing balance (yes/no), as part of the Short Physical
Performance Battery (SPPB).
- Level of activity, using the Vital Connect Healthpatch accelerometer.
- 4-meter walking speed (in m/s), as part of the SPPB.
- Sit-to-stand transfer (in s), as part of the SPPB.
Background summary
Age related diseases pose a burden for both the elderly and society as a whole.
In recent years, evidence has shown that dysfunction of mitochondria plays an
important role in age related diseases, such as Alzheimer*s and Parkinson*s
diseases, diabetes mellitus type 2 and sarcopenia. The mitochondrion is a
central organelle that can drive both cellular life, i.e. by producing energy
in the respiratory chain, and death, i.e. by initiating apoptosis. More
recently, it was demonstrated that dysfunctional mitochondria can be
specifically targeted for elimination by autophagy, a process that has been
termed mitophagy. During aging, there is a progressive decline in the cell
capacity to eliminate its dysfunctional elements by autophagy, as evidenced by
the accumulation of oxidative damage and mutations in mitochondria and the
decrease in autophagic flux. Therefore, restoring levels of autophagy and
mitophagy in the elderly represents an interesting therapeutic approach to
improve mitochondrial function. Most of the compounds that have been identified
to improve mitochondrial function either stimulate mitochondrial biogenesis
(e.g. AICAR, resveratrol, nicotinamide riboside) or the respiratory chain (e.g.
coenzyme Q10), while no specific mitophagy inducer has been identified yet.
A major challenge posed lies in the lack of tools to quantify mitophagy and the
necessity to have accurate measurements to observe an improvement in
mitochondrial function in vivo in humans. The discovery of the dynamic process
of mitophagy represents an important finding towards an effective therapeutic
strategy for aging-related mitochondrial-based conditions. However, since this
is a relatively recent discovery, only a few markers specific mitophagy markers
have been identified to date. These include parkin, an E3 ubiquitin ligase, and
Phosphatase and tensin homolog (PTEN)-induced putative kinase protein 1
(PINK1), two genes in which mutations have been linked to hereditary forms of
Parkinson*s diseases. Under basal conditions, PINK1 is imported into
mitochondria and rapidly turned over by proteolysis. When mitochondria are
dysfunctional, PINK1 accumulates at the surface of the organelle and recruits
Parkin, which can then ubiquitylates mitochondrial proteins. Ubiquitylation is
a universal signal for degradation that is recognized by the autophagy
adaptors, such as sequestosome 1 (SQSTM1/p62), which can then bind to
microtubule-associated protein 1 light chain 3 beta (LC3B), a protein linked to
the autophagosome. The mitochondrion tagged with ubiquitin is then engulfed
into the autophagosome to be degraded by lysosomal enyzmes. Most of the work
related to these biomarkers was performed in neuronal cell lines, because of
its particular relevance for Parkinson*s disease. Therefore, the two most
characterized markers of mitophagy (PINK1 and parkin) are mostly applicable to
neurons. In muscle cells, it has not yet been established what mitophagy
adapters are. In this study, a set of mitophagy biomarkers will be measured in
muscle samples from elderly male and female active and pre-frail subjects, in
order to validate these biomarkers for further research.
Dynamic 31P-MRS is an established method to measure mitochondrial function and
can be considered to be the gold standard for in vivo mitochondrial function
measurement. The correlation between mitophagy and mitochondrial dysfunction in
neurology is fairly established. However, less is known regarding muscle
tissue. Therefore in this study we compare mitochondrial function to level of
mitophagy in muscle tissue.
Study objective
Amazentis (AMZ) has identified the first ingredient that is able to stimulate
mitophagy, namely AZ400, a natural product derived from food. AMZ has conducted
several preclinical studies showing that AZ400 has a strong potential to
improve muscle function in adult mice through the enhancement of mitochondrial
function via mitophagy. The objective for this study is method and diagnostic
assay development for the measurement of mitochondrial function and mitophagy
in human muscle tissue of healthy, active elderly subjects and pre-frail,
sedentary elderly subjects . The main objective is to assess the level of
mitophagy in muscle biopsy tissue of active healthy elderly subjects and
sedentary pre-frail elderly subjects using three different methods, including
(1) histopathology and staining for microtubule-associated protein autophagy
marker Light Chain 3 (LC3), (2) quantification of ubiquitylation of the
mitochondrial fraction, and (3) gene expression.
Study design
Method validation study of biomarkers, parallel group design, with two
consecutive study periods for assessment of day-to-day reproducibility of
measurements.
Study burden and risks
A needle muscle biopsy is a safe and well tolerated method to obtain muscle
tissue. In this study, the muscle biopsy procedure will be performed twice to
determine the reproducibility of mitophagy biomarkers. In a study in elderly
subjects, 87% of subjects indicated that they would undergo a muscle biopsy
again. The type of muscle biopsy in this study was more invasive and more
burdensome than the method proposed in the current study. Knowledge about the
variability is required to determine the validity of the assessments and to
assess the sample size for the phase 1 clinical trial involving AZ400.
Therefore, in our opinion, the benefit of repeating the procedure outweighs the
burden for the subjects. The other techniques to measure mitochondrial
function, including MRI scanning, performed in this study are non-invasive
procedures, that yield only little burden for the subjects.
EPFL Innovation Park, Bâtiment C -
Lausanne 1015
CH
EPFL Innovation Park, Bâtiment C -
Lausanne 1015
CH
Listed location countries
Age
Inclusion criteria
Inclusion criteria for active, healthy subjects;1. 61 years of age or older, inclusive.
2. Healthy male or female subjects. Healthy status is defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis.
3. Body mass index (BMI) between 15 and 35 kg/m2, inclusive.
4. Able to participate and willing to give written informed consent and to comply with the study restrictions.
5. Category 2 or 3 as assessed by the International Physical Activity Questionnaires (IPAQ). Activity level is >= 600 MET (metabolic equivalent unit) - minutes per week.
6. Normal physical performance: normal gait speed, i.e. a walking >= 0.8 m/s in the 4-m walking test.
7. Normal muscle mass: normal skeletal muscle mass index (SMI), measured by Bioimpedance analysis (BIA, for males >= 10.75 kg/m2, for females >= 6.75 kg/m2).
8. Normal muscle strength: handgrip strength (measured with the Jamar dynamometer) of >= 30 kg for males and >= 20 kg for females.;Inclusion criteria for sedentary, pre-frail subjects;1. Sedentary, pre-frail males. Pre-frailty is defined as fulfilling to at least two out of the following three criteria: low physical performance (low gait speed, i.e. a walking speed below 0.8 m/s in the 4-m walking test), low muscle mass (a low skeletal muscle mass index (SMI), measured by Bioimpedance analysis (BIA, for males < 10.75 kg/m2, for females < 6.75 kg/m2)) and/or low muscle strength: handgrip strength (measured with the Jamar dynamometer) < 30 kg for males and < 20 kg for females. Sedentary behaviour is defined as having an activity category of 1 as assessed by the International Physical Activity Questionnaires (IPAQ) (Activity level is < 600 MET (metabolic equivalent unit) - minutes per week).
2. Body mass index (BMI) between 15 and 35 kg/m2, inclusive.
3. Able to participate and willing to give written informed consent and to comply with the study restrictions.
4. 61 years of age or older, inclusive.
Exclusion criteria
Exclusion criteria for active, healthy subjects;1. Presence of any contraindication to have MRI scans performed (e.g. pacemaker, intracranial clips etc.).
2. Having diabetes mellitus or lower extremity peripheral vascular disease, as these conditions may interfere with interpretation of the dynamic 31P-MRS and NIRS of the lower extremity.
3. Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.
4. A history (within 3 months of screening) of alcohol consumption exceeding 3 standard drinks per day on average (1 standard drink = 10 grams of alcohol).
5. Inability to refrain from smoking more than half a pack of cigarettes (or similar for other tobacco products) per day during the course of the study (from screening to End-of-Study [EOS]).
6. A history or presence of allergy to 5-aminolevulinic acid or porphyrins.
7. A history or presence of allergy to lidocaine.
8. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
9. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening.
10. Unwillingness or inability to refrain from consuming alcohol within 48 hours before each visit until the end of that visit.
11. Unwillingness or inability to refrain from consuming 8 or more units of xanthine containing beverages and foods per day during the entire study.
12. Unwillingness or inability to refrain from consuming the following supplements: L-carnitine, creatine, Q10, vitamin A, niacin, folic acid, vitamin C, vitamin E and probiotic- foods and supplements at least two weeks before study enrolment.
13. Unwillingness or inability to have a muscle biopsy performed.;Exclusion criteria for sedentary, pre-frail subjects;1. Presence of any contraindication to have MRI scans performed (e.g. pacemaker, intracranial clips etc.).
2. Having diabetes mellitus or lower extremity peripheral vascular disease, as these conditions may interfere with interpretation of the dynamic 31P-MRS and NIRS of the lower extremity.
3. Participation in a clinical trial within 90 days of screening or more than 4 times in the previous year.
4. A history (within 3 months of screening) of alcohol consumption exceeding 3 standard drinks per day on average (1 standard drink = 10 grams of alcohol).
5. Inability to refrain from smoking more than half a pack of cigarettes (or similar for other tobacco products) per day during the course of the study (from screening to End-of-Study [EOS]).
6. A history or presence of allergy to 5-aminolevulinic acid or porphyrins.
7. A history or presence of allergy to lidocaine.
8. Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening.
9. Loss or donation of blood over 500 mL within three months (males) or four months (females) prior to screening.
10. Unwillingness or inability to refrain from consuming alcohol within 48 hours before each visit until the end of that visit.
11. Unwillingness or inability to refrain from consuming 8 or more units of xanthine containing beverages and foods per day during the entire study.
12. Unwillingness or inability to refrain from consuming the following supplements: L-carnitine, creatine, Q10, vitamin A, niacin, folic acid, vitamin C, vitamin E and probiotic- foods and supplements at least two weeks before study enrolment.
13. Unwillingness or inability to have a muscle biopsy performed.
14. Underlying chronic disease, which, in the opinion of the investigator would interfere with study participation or the validity of the measurements.
15. Unintentional weight loss <=5% of usual body weight during the last 6 months.
16. Anorexia or anorexia-related symptoms
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL53006.056.15 |