Oxygen Nanosensor for Mitochondrial Myopathy

Overseen By Sara Nguyen

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Anti-platelet, Immunosuppressive, Corticosteroids

Disqualifiers: Severe cardiac, pulmonary disease, others

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

Compensation: Varies

Number of Visits: 2

24 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 Oxygen Nanosensor safe for use in humans?

The research on oxygen sensors, including those tested in rabbits, shows that they are stable and functional for long periods, suggesting they are generally safe for monitoring oxygen levels in tissues. However, specific safety data for humans is not provided in the available studies. ^{1 2 3 4 5}

How does the Oxygen Nanosensor treatment for Mitochondrial Myopathy differ from other treatments?

The Oxygen Nanosensor treatment is unique because it uses a genetically encoded sensor to measure oxygen levels inside muscle cells in real-time, helping to understand and manage the oxygen dynamics in mitochondrial myopathy, a condition with no standard treatment. This approach is different from traditional methods as it provides detailed insights into how oxygen is used by cells, which is crucial for addressing the muscle metabolism issues caused by mitochondrial DNA mutations. ^{2 6 7 8 9}

What data supports the effectiveness of the treatment Oxygen Nanosensor for Mitochondrial Myopathy?

Research shows that oxygen therapy can significantly improve muscle metabolism in patients with mitochondrial myopathy, suggesting that treatments enhancing oxygen delivery, like the Oxygen Nanosensor, could be beneficial. ^{6 7 10 11 12}

Who Is on the Research Team?

Zarazuela Zolkipli-Cunningham

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with genetically confirmed mitochondrial myopathy, characterized by exercise intolerance and muscle weakness. Healthy volunteers must be able to walk, do bike exercises, and give informed consent. People are excluded if they don't meet these criteria or can't follow the study protocol.

Inclusion Criteria

I understand the study and agree to participate.

Previously enrolled (or will enroll) in Children's Hospital of Philadelphia (CHOP) Institutional Review Board (IRB) study #08-006177 (Falk, PI) or CHOP IRB #16-013364 (Zolkipli, PI)

I have a genetic condition causing muscle weakness, especially after exercise.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Measurement

Nanosensor muscle oxygen measurement in exercised forearm muscle during handgrip exercise

1 week

1 visit (in-person)

Reproducibility Assessment

Repeat nanosensor measurements to assess reproducibility

1-4 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after measurements

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Oxygen Nanosensor

Trial Overview The trial is testing an electrochemical oxygen nanosensor designed to measure mitochondrial function in human muscle tissue. It aims to distinguish between MM patients and healthy individuals, potentially aiding future diagnosis and treatment of mitochondrial diseases.

How Is the Trial Designed?

Group I: Healthy Controls Experimental Treatment 1 Intervention

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

Group II: Affected MM Cases Experimental Treatment 1 Intervention

Key eligibility criteria for 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.

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

Oxygen therapy significantly improved the inferred maximal ATP synthesis rate by 33% in patients with mitochondrial myopathy (MM), indicating enhanced muscle metabolism during exercise.

In contrast, oxygen supplementation had only a minimal effect (5% improvement) on ATP synthesis in healthy controls, suggesting that patients with MM may uniquely benefit from therapies that increase oxygen availability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients. Trenell, MI., Sue, CM., Thompson, CH., et al.[2022]

A noninvasive tissue oxymeter using near infrared light revealed extensive tissue oxygenation in patients with mitochondrial myopathy, linking oxygen levels to the severity of mitochondrial DNA mutations.

The study suggests that the degree of oxygenation correlates with defects in the oxidative phosphorylation system, which may contribute to the progression of mitochondrial DNA mutations, highlighting the potential for this diagnostic method in managing older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extensive tissue oxygenation associated with mitochondrial DNA mutations. Ozawa, T., Sahashi, K., Nakase, Y., et al.[2004]

In a study involving four normal controls and four patients with mitochondrial disorders, normal individuals maintained stable oxygen levels during exercise, while patients exhibited abnormal oxygenation and slow recovery, indicating impaired oxidative phosphorylation.

The study suggests that noninvasive tissue oximetry can effectively assess the severity of mitochondrial myopathy and exercise intolerance by measuring the imbalance between oxygen delivery and utilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measurement of tissue oxygen consumption in patients with mitochondrial myopathy by noninvasive tissue oximetry. Abe, K., Matsuo, Y., Kadekawa, J., et al.[2019]

A new imaging method using a genetically encoded O2-responsive sensor allows for real-time quantification of oxygen levels in single muscle cells, providing insights into how oxygen dynamics affect muscle metabolism.

The study demonstrates that the measured oxygen gradients correlate with metabolic changes during muscle differentiation, highlighting the importance of oxygen in maintaining muscle mass and function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High resolution spatial investigation of intracellular oxygen in muscle cells. Penjweini, R., Pasut, A., Roarke, B., et al.[2023]

A novel non-invasive method for measuring muscle oxygenation (MOx) in children with anemia showed that higher MOx values correlate with higher hematocrit (Hct) levels, suggesting that MOx could be a relevant indicator for assessing the need for blood transfusions.

In patients with low pre-transfusion MOx, RBC transfusions significantly increased both Hct and MOx, indicating that monitoring MOx could help optimize transfusion decisions and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive assessment of muscle oxygenation may aid in optimising transfusion threshold decisions in ambulatory paediatric patients. Schenkman, KA., Hawkins, DS., Ciesielski, WA., et al.[2019]

A new low-cost, miniaturized implantable electrochemical sensor has been developed for continuous monitoring of hypoxia by detecting pH changes, showing excellent sensitivity and reproducibility in both in vitro and in vivo tests with adult rabbits.

The sensor demonstrated strong performance over 18 months, effectively distinguishing between hypoxia and normoxia, and correlating well with standard monitoring devices, indicating its potential for real-time clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

in vivo Monitoring with micro-implantable hypoxia sensor based on tissue acidosis. Dulay, S., Rivas, L., Miserere, S., et al.[2021]

A new oxygen microsensor with a very small tip diameter (< 3 microns) was developed, allowing for precise monitoring of oxygen levels at single cells and mouse pancreatic islets, with a response time of less than 1 second.

The sensor revealed that pancreatic islets maintain adequate oxygen levels for insulin secretion during glucose stimulation, and it detected dynamic oscillations in oxygen levels, indicating active metabolic processes in response to glucose concentration changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oxygen microsensor and its application to single cells and mouse pancreatic islets. Jung, SK., Gorski, W., Aspinwall, CA., et al.[2019]

This study emphasizes the importance of mitochondrial toxicity in the adverse outcome pathways (AOPs) related to nanomaterials (NMs), suggesting that understanding this mechanism is crucial for assessing NM-induced toxicity.

The research identified existing AOPs in the AOP-Wiki that can be adapted for NMs, but it also highlighted the need for better quality studies that accurately report the physicochemical characteristics of NMs and their mitochondrial effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals. Murugadoss, S., Vinković Vrček, I., Schaffert, A., et al.[2023]

A new protocol for validating implanted oxygen sensors allows for accurate calibration before and after implantation, helping to distinguish between sensor performance and tissue effects on oxygen measurement.

The model developed for this protocol effectively describes how oxygen signals are transferred to the sensor, which aligns with experimental data and enhances the reliability of oxygen concentration readings from implanted sensors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mass transfer and gas-phase calibration of implanted oxygen sensors. Makale, MT., Jablecki, MC., Gough, DA.[2006]

Monocrystalline micro antimony electrodes demonstrated significant sensitivity to changes in tissue oxygen levels in rabbits, with a sensitivity of 21.8 mV for low oxygen levels (0.1 to 1 kPa) and 53 mV for higher levels (1 to 6 kPa).

The unique S-shaped oxygen sensitivity curve observed suggests that the antimony electrodes may interact with both dissolved oxygen and oxygen bound to hemoglobin, potentially allowing for the measurement of oxyhemoglobin dissociation in tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The oxygen sensitivity of a multipoint antimony electrode for tissue pH measurements. A study of the sensitivity for in vivo PO2 variations below 6 kPa. Sjöberg, F., Edwall, G., Lund, N.[2019]

A new chemiresistor sensor made from a poly(Bismarck Brown Y)-reduced graphene oxide nanocomposite effectively detects oxygen levels, showing a linear response across a wide concentration range and a very low detection limit of 3.60 × 10-7 mol L-1.

This sensor allows for real-time monitoring of oxygen consumption in cells, revealing how oxygen levels change during metabolic activity, which can be crucial for studying cellular respiration and mitochondrial function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Chemiresistor Sensor Based on Azo-Polymer and Graphene for Real-Time Monitoring of Mitochondrial Oxygen Consumption. Olean-Oliveira, A., Olean-Oliveira, T., Moreno, ACR., et al.[2020]

A new biosensor has been developed to selectively detect and quantify superoxide anion (SOA) levels, which are important for understanding muscle activity and fatigue.

The biosensor was successfully tested using a xanthine/xanthine oxidase system and later applied to measure SOA release from muscle cells (C2C12 myoblasts and myotubes) when stimulated, demonstrating its potential for studying physiological and pathological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An electrochemical biosensor based on gold microspheres and nanoporous gold for real-time detection of superoxide anion in skeletal muscle tissue. Sadeghian, RB., Ostrovidov, S., Salehi, S., et al.[2020]

Citations

1. Germany pubmed.ncbi.nlm.nih.gov

Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients. [2022]

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

Extensive tissue oxygenation associated with mitochondrial DNA mutations. [2004]

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

Measurement of tissue oxygen consumption in patients with mitochondrial myopathy by noninvasive tissue oximetry. [2019]

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

High resolution spatial investigation of intracellular oxygen in muscle cells. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Non-invasive assessment of muscle oxygenation may aid in optimising transfusion threshold decisions in ambulatory paediatric patients. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

in vivo Monitoring with micro-implantable hypoxia sensor based on tissue acidosis. [2021]

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

Oxygen microsensor and its application to single cells and mouse pancreatic islets. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals. [2023]

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

Mass transfer and gas-phase calibration of implanted oxygen sensors. [2006]

10. England pubmed.ncbi.nlm.nih.gov

The oxygen sensitivity of a multipoint antimony electrode for tissue pH measurements. A study of the sensitivity for in vivo PO2 variations below 6 kPa. [2019]

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

A Chemiresistor Sensor Based on Azo-Polymer and Graphene for Real-Time Monitoring of Mitochondrial Oxygen Consumption. [2020]

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

An electrochemical biosensor based on gold microspheres and nanoporous gold for real-time detection of superoxide anion in skeletal muscle tissue. [2020]