Exercise Therapy for Mitochondrial Disease

Overseen By Daniel McGinn, MSGC

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Investigational agents

Disqualifiers: Cystic fibrosis, Chronic lung disease, others

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

Compensation: Varies

Number of Visits: 3

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how different types of exercise might benefit people with mitochondrial disease, a condition affecting energy production in the body. It compares the effects of regular exercise and a special passive exercise called Periodic Acceleration (pGz), which involves movement without patient effort. The trial has two parts: one includes people with mitochondrial disease who can walk and healthy volunteers, while the other focuses on non-walking patients in intensive care. Individuals diagnosed with mitochondrial disease who experience exercise intolerance and muscle weakness might be suitable candidates, as well as those admitted to a pediatric ICU for more than 24 hours. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that regular exercise is generally safe for people with mitochondrial diseases. In one study, a program with various exercises was well-tolerated by 12 patients with this condition. Another study found that exercise can increase the number of mitochondria (the energy producers in cells) in healthy people and may help reduce symptoms in those with mitochondrial muscle diseases.

Studies indicate that periodic acceleration (pGz) can improve heart function in certain cases. Although detailed safety data for mitochondrial diseases is limited, this technique has shown benefits without major side effects in related research. Researchers are carefully studying both exercise and pGz to ensure safety for all participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this trial because it explores innovative exercise techniques as potential treatments for mitochondrial disease. Unlike traditional treatments that may focus on dietary supplements or medications to support mitochondrial function, this study investigates the effects of conventional exercise and a method called Periodic Acceleration (pGz). pGz is particularly unique because it involves gentle, rhythmic movements that could enhance blood flow and cellular oxygenation, potentially offering benefits without the intensity of regular exercise. This trial could reveal new ways to improve energy metabolism and overall health for those with mitochondrial disorders, offering hope for more effective management strategies.

What evidence suggests that this trial's treatments could be effective for mitochondrial disease?

Research shows that exercise can greatly improve the health of mitochondria, the parts of cells that produce energy. Studies have found that exercise, especially activities like running or cycling, enhances mitochondrial function and increases their number. This can lead to more energy in cells, better exercise ability, and a higher quality of life for people with mitochondrial disease. In this trial, some participants will engage in conventional exercise to assess its impact.

Another method studied in this trial is periodic acceleration (pGz). It has shown potential in aiding muscle recovery and improving blood flow. Although researchers are still learning about its long-term effects on mitochondrial disease, early findings suggest it might help manage symptoms by boosting muscle function. Both exercise and pGz offer hope for improving energy production in cells for those with mitochondrial conditions. ^{3 6 7 8 9}

Who Is on the Research Team?

Zuela Zolkipli-Cunningham, MBChB, MRCP

Principal Investigator

Attending Physician

Are You a Good Fit for This Trial?

This trial is for males and females aged 10-60 with genetically confirmed mitochondrial myopathy, able to perform clinical exercise tests, and can follow study procedures. It excludes pregnant women, those allergic to Lumason®, individuals with severe diseases or conditions that prevent safe participation, recent investigational drug users, non-ambulatory persons, and certain government employees.

Inclusion Criteria

My parents or guardians have agreed to my participation in this study.

I can walk and complete basic exercise tests.

I am between 10 and 60 years old and at least 135 cm tall.

Exclusion Criteria

Pregnant or lactating females

Cognitive impairment that may preclude ability to comply with study procedures

Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intervention

Participants undergo various interventions including CPET, pGz administration through a bed or recliner, and pGz through a Gentle Jogger. Blood draws, vascular ultrasounds, and MRIs are conducted before and after interventions.

3 visits for Aim 1, 2 visits for Aim 2

3 visits (in-person) for Aim 1, 2 visits (in-person) for Aim 2

Follow-up

Participants are monitored for safety and effectiveness after interventions, including measurements of oxygen consumption, heart rate, and other physiological markers.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Conventional Exercise
• Periodic Acceleration (pGz)

Trial Overview

The study examines the effects of conventional (Cardiopulmonary Exercise Testing or pedal exercise) versus passive exercises (pGz Bed) on patients with primary mitochondrial disease compared to healthy volunteers. Part of the research includes critically ill children in a hospital's intensive care unit.

How Is the Trial Designed?

Group I: Aim 2: PICU Patients Experimental Treatment 3 Interventions

All participants in Aim 2 will have the interventions/study visits occur in the same order: Exercise Pedal and Gentle Jogger

Group II: Aim 1: Primary Mitochondrial Disease Patients Experimental Treatment 4 Interventions

The participant has the interventions/study visits occur in a random order: CPET pGz administration through pGz Bed pGz administration through Gentle Jogger

Group III: Aim 1: Healthy Controls Experimental Treatment 4 Interventions

The participant has the interventions/study visits occur in a random order: pGz administration through Gentle Jogger CPET pGz administration through pGz Bed

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

A 12-week resistance training program in a 21-year-old patient with MELAS led to significant improvements in skeletal muscle function, including increases in maximal voluntary torque and muscle activation, indicating that resistance training can enhance muscle performance in this rare condition.

The study also showed that while mitochondrial respiration capacity showed minimal changes, the kinetics of mitochondrial function improved significantly, suggesting that resistance training can positively influence both neuromuscular and mitochondrial adaptations in patients with MELAS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromuscular and Muscle Metabolic Functions in MELAS Before and After Resistance Training: A Case Study. Venturelli, M., Villa, F., Ruzzante, F., et al.[2020]

A 12-week cycle training program significantly improved exercise capacity (VO2max) and muscle enzyme activity in patients with mitochondrial myopathy (MM), indicating that aerobic training can enhance oxidative capacity in these patients.

The training was found to be safe, as it did not alter mtDNA mutation load, muscle morphology, or plasma creatine kinase levels, suggesting that regular supervised aerobic exercise is beneficial for MM patients with specific mitochondrial mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Jeppesen, TD., Schwartz, M., Olsen, DB., et al.[2022]

In mouse models of primary mitochondrial diseases (PMDs), endurance exercise improved mitochondrial function in mice with an mtDNA ND6 mutation, but had little to no positive effects in those with CO1 or ND5 mutations, highlighting the variability in exercise response based on specific genetic mutations.

For mice with a deficiency in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise worsened heart conditions, indicating that exercise may not be beneficial for all PMD patients and emphasizing the need for personalized approaches based on genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial mutations alter endurance exercise response and determinants in mice. Schaefer, PM., Rathi, K., Butic, A., et al.[2022]

In a study involving 21 patients with various mitochondrial diseases and McArdle's disease, muscle ATP and phosphocreatine levels remained similar to controls both at rest and after exercise, indicating that these energy stores are not significantly affected by these conditions.

Patients with mitochondrial diseases showed lower resting lactate levels, but their lactate increased more during exercise compared to controls, particularly in those with adPEO and MELAS, while McArdle's disease patients exhibited a decrease in lactate during exercise, highlighting distinct metabolic responses to physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATP, phosphocreatine and lactate in exercising muscle in mitochondrial disease and McArdle's disease. Löfberg, M., Lindholm, H., Näveri, H., et al.[2019]

Patients with mitochondrial disorders (PEO and MELAS) showed prolonged blood lactate accumulation after exercise, indicating impaired metabolic response even in cases of mild exercise intolerance.

The study suggests that cardiopulmonary exercise testing can be a valuable diagnostic tool for assessing exercise capacity and metabolic stress in patients with mitochondrial myopathies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. Lindholm, H., Löfberg, M., Somer, H., et al.[2014]

An 8-week exercise program combining aerobic, resistance, and inspiratory muscle training was safe and well-tolerated by 12 patients with mitochondrial disease, showing a high adherence rate of 94%.

The intervention led to significant improvements in aerobic power, muscle strength, and the ability to perform daily activities, as well as positive changes in body composition, indicating its efficacy in enhancing physical capacity for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health Benefits of an Innovative Exercise Program for Mitochondrial Disorders. Fiuza-Luces, C., Díez-Bermejo, J., Fernández-DE LA Torre, M., et al.[2019]

A 14-week endurance training program significantly improved exercise tolerance, peak work capacity, and quality of life in eight patients with mitochondrial myopathies, without affecting the level of deleted mitochondrial DNA (mtDNA).

Detraining for 14 weeks led to a decline in these improvements, highlighting the importance of continued physical activity for maintaining exercise capacity and quality of life in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Taivassalo, T., Gardner, JL., Taylor, RW., et al.[2019]

A 14-week aerobic training program in 10 patients with mitochondrial myopathies led to significant improvements in physical performance, including a 20-30% increase in peak work and oxidative capacities, indicating enhanced muscle function.

Despite these positive outcomes, genetic analysis revealed that the proportion of functional wild-type mitochondrial DNA did not increase and may have even decreased in some patients, raising concerns about the long-term effects of training on mitochondrial genetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Taivassalo, T., Shoubridge, EA., Chen, J., et al.[2019]

Over 20% of the 1164 mitochondrial patients studied reported exercise intolerance, indicating that this is a common and significant symptom in this population.

Specific muscle fiber characteristics, such as ragged red fibers and COX-negative fibers, are more frequently found in patients with exercise intolerance, suggesting a potential link between these features and the symptom, while lactate levels were not predictive.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatigue and exercise intolerance in mitochondrial diseases. Literature revision and experience of the Italian Network of mitochondrial diseases. Mancuso, M., Angelini, C., Bertini, E., et al.[2022]

Endurance exercise training in a mouse model of mitochondrial myopathy significantly increased levels of PGC-1alpha in muscle, leading to enhanced mitochondrial biogenesis and improved ATP production.

This exercise regimen not only delayed the onset of myopathy symptoms but also extended the lifespan of the mice, suggesting that promoting mitochondrial function through exercise could be a promising therapeutic strategy for patients with mitochondrial disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endurance exercise is protective for mice with mitochondrial myopathy. Wenz, T., Diaz, F., Hernandez, D., et al.[2022]

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