Oxygen Nanosensor for Mitochondrial Myopathy
Recruiting in Palo Alto (17 mi)
Overseen byZarazuela Zolkipli-Cunningham
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Children's Hospital of Philadelphia
Must not be taking: Anti-platelet, Immunosuppressive, Corticosteroids
Disqualifiers: Severe cardiac, pulmonary disease, others
No Placebo Group
Trial Summary
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.
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.
12345Is 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.
678910How 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.
2471112Eligibility Criteria
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.
I am between 18 and 65 years old.
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)
+5 more
Trial Timeline
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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Healthy ControlsExperimental Treatment1 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 CasesExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The Children's Hospital of PhiladelphiaPhiladelphia, PA
Loading ...
Who Is Running the Clinical Trial?
Children's Hospital of PhiladelphiaLead Sponsor
National Institutes of Health (NIH)Collaborator
National Institute of Neurological Disorders and Stroke (NINDS)Collaborator
References
Supplemental oxygen and muscle metabolism in mitochondrial myopathy patients. [2022]Patients with mitochondrial myopathy (MM) have a reduced capacity to perform exercise due to a reduced oxidative capacity. We undertook this study to determine whether skeletal muscle metabolism could be improved with oxygen therapy in patients with MM. Six patients with MM and six controls, matched for age, gender and physical activity, underwent (31)P-magnetic resonance spectroscopy ((31)P-MRS) examination. (31)P-MR spectra were collected at rest and in series during exercise and recovery whilst breathing normoxic (0.21 O(2)) or hyperoxic (1.0 O(2)) air. At rest, MM showed an elevated [ADP] (18 +/- 3 micromol/l) and pH (7.03 +/- 0.01) in comparison to the control group (12 +/- 1 micromol/l, 7.01 +/- 0.01) (P 0.05). Inferred maximal ATP synthesis rate improved by 33% with oxygen in MM (21 +/- 3 vs. 28 +/- 5 mmol/(l min), P 0.05). We conclude that oxygen therapy is associated with significant improvements in muscle metabolism in patients with MM. These data suggest that patients with MM could benefit from therapies which improve the provision of oxygen.
Extensive tissue oxygenation associated with mitochondrial DNA mutations. [2004]Extensive tissue oxygenation in the mitochondrial myopathy patients caused by the mitochondrial DNA mutations was first demonstrated noninvasively by a tissue oxymeter measuring near infrared light. The extent of oxygenation of the tissue due to dysfunction of mitochondria correlated with the seriousness of mitochondrial DNA mutations resulting in defects in oxidative phosphorylation system, and causing suppressed oxygen utilization. Such oxygen stress furthers mitochondrial DNA mutations during the progressive course of the disease. This noninvasive diagnosis will find useful application in the diagnosis and management of patients of advanced age.
Measurement of tissue oxygen consumption in patients with mitochondrial myopathy by noninvasive tissue oximetry. [2019]We measured oxygen consumption in the exercising lower limb by using noninvasive tissue oximetry with the near-infrared spectra of hemoglobin in the quadriceps muscle during bicycle ergometer exercise in four normal controls and three patients with chronic progressive external ophthalmoplegia (CPEO) as well as one patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Normal controls showed constant oxygenation during exercise and a rapid recovery after exercise. However, all four patients with mitochondrial myopathy showed abnormal oxygenation during exercise and a slow recovery afterward. The results reflected the defect in oxidative phosphorylation and the impairment in oxygen utilization in those patients. The distinctive patterns of imbalance between oxygen delivery and utilization correlated well with the severity of mitochondrial myopathy as judged by the sum of the serum lactate and pyruvate content during exercise. Noninvasive tissue oximetry may be useful to measure the severity of myopathy and exercise intolerance in patients with mitochondrial myopathy.
High resolution spatial investigation of intracellular oxygen in muscle cells. [2023]Molecular oxygen (O 2 ) is one of the most functionally relevant metabolites. O 2 is essential for mito-chondrial aerobic respiration. Changes in O 2 affect muscle metabolism and play a critical role in the maintenance of skeletal muscle mass, with lack of sufficient O 2 resulting in detrimental loss of muscle mass and function. How exactly O 2 is used by muscle cells is less known, mainly due to the lack of tools to address O 2 dynamics at the cellular level. Here we discuss a new imaging method for the real time quantification of intracellular O 2 in muscle cells based on a genetically encoded O 2 -responsive sensor, Myoglobin-mCherry. We show that we can spatially resolve and quantify intracellular O 2 concentration in single muscle cells and that the spatiotemporal O 2 gradient measured by the sensor is linked to, and reflects, functional metabolic changes occurring during the process of muscle differentiation.
Non-invasive assessment of muscle oxygenation may aid in optimising transfusion threshold decisions in ambulatory paediatric patients. [2019]To assess the potential utility of a novel non-invasive muscle oxygen measurement to determine the presence of muscle hypoxia in patients with anaemia.
in vivo Monitoring with micro-implantable hypoxia sensor based on tissue acidosis. [2021]Hypoxia is a common medical problem, sometimes difficult to detect and caused by different situations. Control of hypoxia is of great medical importance and early detection is essential to prevent life threatening complications. However, the few current methods are invasive, expensive, and risky. Thus, the development of reliable and accurate sensors for the continuous monitoring of hypoxia is of vital importance for clinical monitoring. Herein, we report an implantable sensor to address these needs. The developed device is a low-cost, miniaturised implantable electrochemical sensor for monitoring hypoxia in tissue by means of pH detection. This technology is based on protonation/deprotonation of polypyrrole conductive polymer. The sensor was optimized in vitro and tested in vivo intramuscularly and ex vivo in blood in adult rabbits with respiration-induced hypoxia and correlated with the standard device ePOCTM. The sensor demonstrated excellent sensitivity and reproducibility; 46.4 ± 0.4 mV/pH in the pH range of 4-9 and the selectivity coefficient exhibited low interference activity in vitro. The device was linear (R2 = 0.925) with a low dispersion of the values (n = 11) with a cut-off of 7.1 for hypoxia in vivo and ex vivo. Statistics with one-way ANOVA (α = 0.05), shows statistical differences between hypoxia and normoxia states and the good performance of the pH sensor, which demonstrated good agreement with the standard device. The sensor was stable and functional after 18 months. The excellent results demonstrated the feasibility of the sensors in real-time monitoring of intramuscular tissue and blood for medical applications.
Oxygen microsensor and its application to single cells and mouse pancreatic islets. [2019]An oxygen microsensor with a
Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals. [2023]The Adverse Outcome Pathway (AOP) framework plays a crucial role in the paradigm shift of toxicity testing towards the development and use of new approach methodologies. AOPs developed for chemicals are in theory applicable to nanomaterials (NMs). However, only subtle efforts have been made to integrate information on NM-induced toxicity into existing AOPs. In a previous study, we identified AOPs in the AOP-Wiki associated with the molecular initiating events (MIEs) and key events (KEs) reported for NMs in scientific literature. In a next step, we analyzed these AOPs and found that mitochondrial toxicity plays a significant role in several of them at the molecular and cellular levels. In this study, we aimed to generate hypothesis-based AOPs related to NM-induced mitochondrial toxicity. This was achieved by integrating science-based information collected on NM-induced mitochondrial toxicity into all existing AOPs in the AOP-Wiki, which already includes mitochondrial toxicity as a MIE/KE. The results showed that several AOPs in the AOP-Wiki related to the lung, liver, cardiovascular and nervous system, with extensively defined KEs and key event relationships (KERs), could be utilized to develop AOPs that are relevant for NMs. Our results also indicate that the majority of the studies included in our literature review were of poor quality, particularly in reporting NM physico-chemical characteristics, and NM-relevant mitochondrial MIEs were scarcely reported. This study highlights the potential role of NM-induced mitochondrial toxicity in human-relevant adverse outcomes and identifies useful AOPs in the AOP-Wiki for the development AOPs that are relevant for NMs.
Mass transfer and gas-phase calibration of implanted oxygen sensors. [2006]A protocol is described for validation of implanted oxygen sensors, in which sensors are calibrated in the gas phase where concentration boundary layers are absent. Calibration prior to sensor implantation and confirmation after sensor explantation allows separation of tissue mass transfer effects from sensor variance and drift. A model is given here that describes the oxygen-dependent signal current in terms of oxygen mass transfer to the sensor, permeability of the sensor membrane, and electrode area. The parameter used in the model to describe mass transfer to implanted sensors is consistent with experimental observations and allows comparisons with nonimplanted sensors. This method provides a bridge between the complementary approaches of empirical calibration and model-based calculation for determining oxygen concentration from the sensor response.
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]Monocrystalline micro antimony electrodes in a multipoint arrangement as described by Lund et al. were placed on the skeletal muscle surface of the rabbit. Tissue oxygen levels were measured simultaneously with the MDO (Mehrdraht Dortmund Oberfläche) oxygen electrode. The sensitivity for variations in tissue PO2 (PO2(t)) was evaluated for the antimony metal-metal oxide sensor. The sensitivity (delta E/delta log10 PO2)+/- SE was found to be 21.8 +/- 1.2 mV in the interval between 0.1 kPa and 1 kPa and 53 +/- 5 mV in the interval between 1 kPa and 6 kPa. These results are not consistent with the oxygen sensitivity of monocrystalline antimony described in vitro, but are in agreement with the findings of Nilsson & Edwall. A plausible explanation for the S-shaped oxygen sensitivity curve of antimony at oxygen levels below 10 kPa could be an interaction, at the electrode surface, between the dissolved oxygen and the oxygen bound to haemoglobin. If this is the case, the use of an antimony electrode would make possible the determination of the dissociation of oxyhaemoglobin in tissues.
A Chemiresistor Sensor Based on Azo-Polymer and Graphene for Real-Time Monitoring of Mitochondrial Oxygen Consumption. [2020]In the present study, a chemiresistor sensor based on a poly(Bismarck Brown Y)-reduced graphene oxide nanocomposite was developed to analyze the respiratory capacity of the constituent complexes of the electron transport chain. The sensorial platform was characterized using electrochemical impedance spectroscopy, and oxygen detection was accomplished by measuring the resistive properties of the sensor at fixed AC frequency. The impedance decreased significantly in response to small variations of the O2 concentrations tested up to saturation of the electrolyte solution with molecular oxygen. The resistive response of the sensor at 0.1 Hz was linear over the oxygen concentration range from 1.17 × 10-5 mol L-1 to 1.02 × 10-3 mol L-1, with a detection limit of 3.60 × 10-7 mol L-1. Using the new O2 sensing platform, we monitored gradients in static cultures of adherent cells exposed to graded oxygen both at rest and upon metabolic stimulation. Under high dissolved oxygen conditions, the respiration of resting cells dictated that local O2 was moderately reduced, while cell metabolic stimulation triggered a major redistribution of O2. The usefulness of the developed sensor was demonstrated by continuous monitoring of mitochondrial oxygen consumption in various biologic applications.
An electrochemical biosensor based on gold microspheres and nanoporous gold for real-time detection of superoxide anion in skeletal muscle tissue. [2020]Superoxide anion (SOA) as a member of reactive oxygen species (ROS) group is involved in various physiological and pathological states. For instance, generation of SOA is known to increase with skeletal muscle contractile activity and fatigue. It is therefore important to selectively detect and accurately quantify the release of SOA within both physiological and pathological levels. We report fabrication and characterization of a cytochrome-c functionalized SOA biosensor built on commercially available miniaturized screen-printed electrodes made of gold microspheres. The device was first tested and calibrated in a xanthine/xanthine oxidase (XOD) system and then employed to detect SOA release from C2C12 myoblasts and myotubes upon stimulation with PMA.