Nanosensor for Mitochondrial Myopathy

Overseen By Daniel McGinn, MS, LCGC

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Aspirin, Immunosuppressants, Corticosteroids

Disqualifiers: Severe cardiac disease, Severe pulmonary disease, Bleeding disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: up to 4 hours

96 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Past mitochondrial disease treatment studies have been unsuccessful in determining treatment efficacy, and a major factor has been the lack of validated biomarkers in mitochondrial myopathy (MM). There is currently a growing number of potential new treatments to be tested through MM clinical intervention trials, which has created a pressing need for quantitative biomarkers that reliably reflect MM disease severity, progression, and therapeutic response. The purpose of the study is to measure the efficacy of an electrochemical oxygen nanosensor to measure in vivo mitochondrial function in human muscle tissue, and its ability to discriminate MM patients from healthy volunteers. The data and results from this nanosensor study may contribute to current and future research, including improved diagnostic and therapeutic approaches for patients with mitochondrial disease.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on daily aspirin or anti-platelet therapy that can't be stopped temporarily, or if you are on chronic steroid treatment.

Is the Nanosensor treatment safe for humans?

There is no specific safety data available for the Nanosensor treatment in humans from the provided research articles. ^{1 2 3 4 5}

How is the Nanosensor treatment for mitochondrial myopathy different from other treatments?

The Nanosensor treatment is unique because it uses mitochondria-based biosensors to detect ion fluxes, which can help in developing drugs that target ion channels. This approach is novel compared to traditional treatments, as it focuses on the mitochondrial ion dynamics and their role in energy production and disease. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment Nanosensor for mitochondrial myopathy?

The research on aerobic training for patients with mitochondrial myopathies shows that exercise can improve muscle function and reduce fatigue, suggesting that treatments enhancing mitochondrial function, like the Nanosensor, might also be beneficial. Additionally, the study on Olesoxime, a compound that enhances mitochondrial function, showed improvements in muscle quality and reduced muscle damage in a model of muscular dystrophy, indicating potential benefits for similar mitochondrial-targeted treatments. ^{1 3 7 11 12}

Who Is on the Research Team?

Zarazuela Zolkipli-Cunningham, MBChB, MRCP

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for healthy adults and those with genetically-confirmed mitochondrial myopathy (MM), aged 18 to 65, who can consent, understand the protocol, walk on their own, and do bicycle ergometry. Excluded are non-ambulatory individuals, pregnant women, immune-compromised persons or those on immunosuppressive drugs, people with severe skin infections or neutropenia, chronic steroid users, certain myopathy cases other than MM.

Inclusion Criteria

I am 18-65 with confirmed mitochondrial myopathy, can walk, and can do a bike test.

Exclusion Criteria

I cannot walk on my own.

Pregnant

Immune deficiency, use of immunosuppressive drugs, history of severe skin or soft tissue infections, history of neutropenia, chronic steroid treatment, hypertrophic scars and keloids, known inherited myopathy, allergy to lidocaine, cognitive impairment, inability to comply with study protocol, individuals from vulnerable populations, inability to speak and/or read English proficiently, employed by the U.S. Department of Defense

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

up to 40 days

Treatment

Nanosensor muscle oxygen measurement in exercised forearm muscle during handgrip exercise

up to 4 hours

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including self-reported pain and fatigue assessments

up to 40 days

What Are the Treatments Tested in This Trial?

Interventions

• Nanosensor

Trial Overview The study tests an electrochemical oxygen nanosensor's ability to measure mitochondrial function in human muscle tissue of MM patients versus healthy volunteers. It aims to establish a reliable biomarker for disease severity and treatment response in mitochondrial diseases.

How Is the Trial Designed?

Group I: Affected Mitochondrial Myopathy (MM) Cases Experimental Treatment 1 Intervention

Key eligibility criteria for Mitochondrial Myopathy (MM) cases includes physically-capable adults (male and females, ages 18 to 65 years, inclusive) with genetically-confirmed MM with predominant symptoms of myopathy as expressed by exercise intolerance and muscle weakness and fatigue.

Group II: Healthy Controls Active Control 1 Intervention

Adult healthy volunteers will be individually matched with corresponding Mitochondrial Myopathy cases based on age, biological sex, and body mass index.

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

In a study on D2.mdx mice with Duchenne muscular dystrophy, the compound Olesoxime was found to preserve mitochondrial creatine sensitivity in limb and respiratory muscles during early stages of the disease, suggesting it may help mitigate mitochondrial stress.

Olesoxime treatment led to reduced muscle damage (as indicated by lower serum creatine kinase levels) and improved muscle quality, including better recovery of diaphragm force and maintenance of lean muscle volume, although it did not significantly affect grip strength or voluntary activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial creatine sensitivity is lost in the D2.mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime. Bellissimo, CA., Delfinis, LJ., Hughes, MC., et al.[2023]

In a study of 10 patients with mitochondrial myopathies who underwent 8 weeks of moderate-intensity aerobic training, their estimated aerobic capacity increased by 30%, indicating significant improvement in physical fitness.

The training also led to a 30% reduction in blood lactate levels and over 60% improvement in muscle recovery after exercise, suggesting that aerobic training can enhance both biochemical and functional measures in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of aerobic training in patients with mitochondrial myopathies. Taivassalo, T., De Stefano, N., Argov, Z., et al.[2019]

Patients with mitochondrial myopathies (MM) commonly experience exercise intolerance, characterized by reduced maximal oxygen consumption (VO2max) and increased carbon dioxide production (VCO2), which can be assessed through standard exercise testing protocols.

Aerobic exercise testing, particularly with measurements of oxygen consumption, is effective for diagnosing and monitoring MM, showing good sensitivity (0.63-0.75) and specificity (0.70-0.90), and can be enhanced with additional techniques like near-infrared spectroscopy and magnetic resonance spectroscopy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise testing as a diagnostic entity in mitochondrial myopathies. Tarnopolsky, M.[2005]

Serum FGF21 (S-FGF21) levels are significantly elevated in patients with primary mitochondrial myopathy, particularly in those with mitochondrial translation defects or mtDNA deletions, making it a specific biomarker for these conditions.

While S-FGF21 shows high specificity (89.3%) for diagnosing mitochondrial myopathy, it does not rule out other types of mitochondrial defects, highlighting the need for comprehensive diagnostic approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Lehtonen, JM., Forsström, S., Bottani, E., et al.[2022]

In a study of 118 patients with primary mitochondrial myopathy (PMM), various functional tests and biomarkers were found to significantly differ from healthy controls, indicating their potential as reliable outcome measures for monitoring PMM.

Functional measures correlated with patients' reported fatigue and pain, suggesting that these assessments can help evaluate the impact of PMM on daily life and may be useful in clinical trials to track treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary mitochondrial myopathy: Clinical features and outcome measures in 118 cases from Italy. Montano, V., Gruosso, F., Carelli, V., et al.[2022]

A study of 27,140 reported cases of rhabdomyolysis identified 14 drugs, including fenofibrate and risperidone, that are linked to mitochondrial toxicity, suggesting a common mechanism for drug-induced muscle damage.

Using murine L6 cells and human skeletal muscle-derived cells, researchers confirmed that these drugs cause significant mitochondrial dysfunction, indicating that the L6 model could be a useful and cost-effective tool for screening potential myotoxic drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing In Vitro Models to Define the Role of Direct Mitochondrial Toxicity in Frequently Reported Drug-Induced Rhabdomyolysis. Bin Dayel, FF., Alfirevic, A., Chadwick, AE.[2023]

In a study involving six patients with mitochondrial myopathy, bezafibrate was found to be safe with no significant adverse effects, and it improved mitochondrial function by reducing complex IV-immunodeficient muscle fibers and enhancing cardiac function over 12 weeks.

However, the treatment also led to increased serum biomarkers associated with mitochondrial disease and changes in fatty acid and amino acid metabolism, suggesting potential long-term risks that need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic effects of bezafibrate in mitochondrial disease. Steele, H., Gomez-Duran, A., Pyle, A., et al.[2022]

In a phase-3 clinical trial involving 218 participants with primary mitochondrial myopathies, elamipretide did not show significant improvement in walking distance or fatigue levels compared to placebo after 24 weeks.

Despite the lack of efficacy in improving primary endpoints, elamipretide was well-tolerated, with most adverse events being mild to moderate, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Karaa, A., Bertini, E., Carelli, V., et al.[2023]

This study successfully demonstrated that mitochondria-based piezosensors can detect ion fluxes through mitochondrial K+-ion channels, which could be useful for drug development targeting these channels.

The research showed that these sensors can respond to changes in ion dynamics and mitochondrial behavior, even when using a polypyrrole binding film, indicating their potential for studying drug effects at very low concentrations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondria-based biosensors with piezometric and RELS transduction for potassium uptake and release investigations. Stobiecka, M., Jakiela, S., Chalupa, A., et al.[2017]

Oligomycin-inhibited mitochondria-modified electrodes can effectively sense nitroaromatics by decoupling the inhibition of pyruvate metabolism, showcasing a novel method for detecting these compounds.

These electrodes can function as both traditional electrochemical sensors and self-powered sensors in a pyruvate/air biofuel cell, indicating their versatility in practical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitroaromatic actuation of mitochondrial bioelectrocatalysis for self-powered explosive sensors. Germain, MN., Arechederra, RL., Minteer, SD.[2009]

The French network of mitochondrial disease diagnostic centers identified significant variability in respiratory chain spectrophotometric assay results due to differing protocols, which can complicate comparisons between centers.

To address this issue, the network standardized and optimized testing protocols, leading to improved consistency in diagnostic results across multiple centers, with experimental data and protocols made freely accessible online.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and implementation of standardized respiratory chain spectrophotometric assays for clinical diagnosis. Medja, F., Allouche, S., Frachon, P., et al.[2019]

The new lab-on-a-chip device for mitochondrial functional assays requires significantly less mitochondrial protein—up to 1000 times less—than traditional methods, making it more accessible for research.

This second-generation system shows improved sensitivity and durability, allowing for better detection of changes in mitochondrial membrane potential, which is crucial for studying degenerative diseases and aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wafer-scale mitochondrial membrane potential assays. Lim, TS., Davila, A., Zand, K., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Mitochondrial creatine sensitivity is lost in the D2.mdx model of Duchenne muscular dystrophy and rescued by the mitochondrial-enhancing compound Olesoxime. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Effects of aerobic training in patients with mitochondrial myopathies. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Exercise testing as a diagnostic entity in mitochondrial myopathies. [2005]

4. United States pubmed.ncbi.nlm.nih.gov

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Primary mitochondrial myopathy: Clinical features and outcome measures in 118 cases from Italy. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Developing In Vitro Models to Define the Role of Direct Mitochondrial Toxicity in Frequently Reported Drug-Induced Rhabdomyolysis. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Metabolic effects of bezafibrate in mitochondrial disease. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Mitochondria-based biosensors with piezometric and RELS transduction for potassium uptake and release investigations. [2017]

10. United States pubmed.ncbi.nlm.nih.gov

Nitroaromatic actuation of mitochondrial bioelectrocatalysis for self-powered explosive sensors. [2009]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Development and implementation of standardized respiratory chain spectrophotometric assays for clinical diagnosis. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Wafer-scale mitochondrial membrane potential assays. [2021]