Mitochondrial diseases are a group of disorders that arise as a result of poorly functioning mitochondria, which fail to produce sufficient energy for the body.

When the mitochondria do not work properly, cells do not have enough energy to function properly—this results in a mitochondrial disease. Depending on which organ symptom is affected, symptoms may include loss of motor control, muscle weakness and pain, gastrointestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual or hearing problems, lactic acidosis, developmental delays, and susceptibility to infection.

According to the Cleveland Clinic, one in 5,000 individuals has a genetic mitochondrial disease. These disorders are caused by errors in DNA. DNA is the blueprint that instructs the body’s growth, development, and maintenance. Most DNA is found within the nucleus of the cell; however, a smaller amount of DNA is found within the cell’s mitochondria.

In fact, the mitochondria are the only components of the cell, other than the nucleus, to contain functioning genes.

In addition to genetic mitochondrial disorders, other health conditions and lifestyle/environmental factors can lead to secondary mitochondrial dysfunction diseases. These disorders include autism, Parkinson’s disease, Alzheimer’s disease, muscular dystrophy, Lou Gehrig’s disease, diabetes, and cancer. With the number and type of symptoms and organ systems involved, mitochondrial diseases are often mistaken for other, more common, diseases.

How are Mitochondrial Diseases Diagnosed?

Because mitochondrial diseases affect so many different organs of the body, and patients have so many different symptoms, mitochondrial diseases are difficult to diagnose. There is no single laboratory or diagnostic test used to confirm the diagnosis of a mitochondrial disease.

The first steps towards obtaining a diagnosis typically include undergoing a series of thorough tests including neurological and metabolic examinations that include blood and urine tests. A cerebral spinal fluid test (spinal tap) may also be required for patients with neurological symptoms.

Additional tests may be ordered depending on a patient’s symptoms. These include: Magnetic resonance imagine (MRI) or spectroscopy (MRS) for neurological symptoms, retinal exam or electroretinogram (ERG) for vision symptoms, electrocardiogram (EKG) or echocardiogram for symptoms of heart disease, audiogram or auditory-brainstem evoked responses (ABER) for hearing symptoms, blood test to detect thyroid dysfunction, and blood tests to perform genetic DNA testing. Biopsies of skin and muscle tissue may also be performed.

Mitochondrial Diagnostic Testing

Diagnosing mitochondrial disease can be a lengthy process and some tests are more accurate than others. A referral to a physician who specialize in these diseases is critical to making the diagnosis.

Muscle biopsy and genetic testing are most commonly used in the clinical setting for diagnosing mitochondrial disease. P³¹NMR Scanning has been effective in cancer diagnosis and is now being used as a specialized test to evaluate lactic acid build-up in mitochondrial disease. On the forefront of cutting-edge research, the Seahorse Analyzer is expanding the scope of mitochondrial dysfunction assessment in the study of cellular metabolism.

Muscle Biopsy

Biochemical testing of muscle fibers obtained from muscle biopsies can determine if mitochondria are functioning properly. Muscle biopsies are performed to examine tissue that is considered highly energy dependent. During a muscle biopsy, a small sample of muscle tissue is removed and inspected; histological examination looks at the structure of the muscle and its characteristics, especially looking for "ragged red fibers". However, histology can be normal in some patients suffering from mitochondrial disease. The energy production pathway can also be examined through study of the enzymes. Drawbacks exist in this testing because it can produce false positive or negative readings. Muscle biopsies are invasive procedures and when done on children require general anesthesia.

Mitochondrial or Nuclear DNA Genetic Testing

DNA genetic tests can be performed on most tissues, for example, from a blood

sample or muscle/liver biopsy. Genetic tests may identify a known disease-causing mutation(s) in the nuclear DNA or in the mitochondrial DNA. If a mutation is identified and a diagnosis is confirmed, this information may provide knowledge about the progression of the disease, determine possible treatments for specific associated symptoms, and also provide information as to whether other family members should be tested.

P³¹NMR Scanning

The P³¹NMR scan is a multinuclear magnetic resonance spectroscopy (MRS) that measures the ATP-ADP ration in vivo. This test can been used to measure brain lactic acid, the antioxidant glutathione (GSH), several high-energy phosphates (e.g. ATP, PCr), and other metabolites in mitochondrial disorders. Simply put, P³¹NMR scanning is able to directly measure the level of ATP in tissues. Since ATP is the energy currency molecule of the cell, an ATP deficiency may provide evidence that indicates a defect in mitochondrial functioning.

The Seahorse Analyzer

The Seahorse XF Extracellular Flux Analyzer enables the direct measurement of mitochondrial functioning and reserve energy-generating capacity from intact cells such as white blood cells obtained from a peripheral blood draw. This powerful technology is currently only available in the research setting. It would be a great step forward if it could be integrated into clinical use in the future.

During the past decade, the number of mitochondrial disease research publications has increased exponentially from less than 100 in 2004 to over 1400 in 2014. The field of mitochondrial disease research is rapidly expanding, with new and significant links of mitochondrial function to human disease. The weight of evidence linking mitochondrial dysfunction to multiple diseases will hopefully lead to better testing methods, and eventually, to new and effective treatments.

Raptor Pharmaceuticals is dedicated to developing medicines that alter cellular metabolic pathways for patients with rare, debilitating, and potentially fatal diseases, including inherited mitochondrial disorders. Raptor has two FDA-approved medications: RP103 (PROCYSBI) and MP376 (QUINSAIR). RP103 was the first brought to market for the treatment of Nephropathic Cystinosis, a rare metabolic disease. It is now being studied for an additional indication in the inherited mitochondrial disease, Leigh Syndrome.

About Leigh Syndrome

Leigh syndrome is a severe neurological disorder caused by genetic defects in mitochondrial or nuclear DNA affecting respiratory function that typically results in death within the first decade of life. The condition causes increased production of free radicals, which disrupts mitochondrial electron transport and affects cellular function in a variety of tissues. Typically observed during the first year of life, Leigh syndrome is characterized by a failure to thrive, lack of coordination, involuntary and sustained muscle contraction, muscle wasting, and multiple organ failure. Currently, there are no approved treatments for Leigh syndrome.

RP103 for the Treatment of Mitochondrial Diseases

Raptor is currently conducting a Phase 2/3 clinical trial to test the safety and efficacy of RP103 in children with Leigh Syndrome and other mitochondrial disorders.

RP103 is believed to increase mitochondrial glutathione, which acts as a scavenger for free radicals in the body. Free radicals are a byproduct of mitochondrial energy production and place stress on cells. In patients with mitochondrial dysfunction, these free radicals are produced at dangerously high levels. By increasing levels of the antioxidant glutathione in the mitochondria, RP103 may reduce the toxic stress typically associated with mitochondrial disorders.

Raptor Pharmaceutical’s Clinical Development Pipeline

Raptor has two active clinical development programs based on its proprietary formulations of cysteamine bitartrate.

RP103 for the potential treatment of:

• Huntington’s disease, an inherited neurodegenerative disease
• Mitochondrial diseases, including Leigh syndrome

Raptor also has two active clinical development programs in expanded indications for MP-376.

• Bronchiectasis (BE) lung infections
• Mycobacteria (NTM) lung Infections

Raptor’s has one further ongoing clinical development program:

• Convivia® (oral 4-methylpyrazole) for the potential management of acetaldehyde toxicity due to ALDH2 deficiency, an inherited metabolic disorder (Phase 2)

With no currently available treatment for Leigh Syndrome, hopes are running high for a successful outcome of Raptor’s RP103-MITO-001 trial. "Leigh syndrome is one of the most devastating of mitochondrial disorders and the RP103-MITO-001 trial will explore a new mechanism of action against this deadly illness," said the trial's lead investigator, Bruce H. Cohen, M.D., Professor of Pediatrics and Director of Neurology at Akron Children's Hospital.

Edison Pharmaceuticals is one of a new group of pharmaceutical companies developing drug treatments for inherited mitochondrial diseases such as Leigh syndrome, Friederich’s ataxia, Leber’s hereditary optic neuropathy (LHON), and acquired mitochondrial dysfunction in Parkinson's disease and ALS.

Inherited Mitochondrial Disease

Inherited mitochondrial diseases are genetic disorders caused by defects in the cells’ ability to make and regulate energy. Due to the role mitochondria plays in the generation and regulation of energy metabolism, mitochondrial diseases affect all organ systems. Most often, these conditions cause impairments in the neurological, cardiovascular, endocrine, hepatic, muscular, and renal systems and can lead to death.

Treating Mitochondrial Disease with Redox Therapy

Edison Pharmaceuticals’ research efforts are focused on the control of cellular energy and metabolism through a class of drugs called “redox” drugs. Mitochondrial diseases are caused by defects in DNA electron transfer. Edison is targeting treatments that regulate the flow of electrons, essential to the generation and regulation of energy. Beyond mitochondrial disease, Edison plans to apply this same knowledge to the development of treatments for other neurological diseases with shared disease mechanisms.

Edison’s Drug Pipeline

EPI-743

EPI-743, also known as Vincerinone, is a drug candidate in clinical development for inherited mitochondrial diseases. EPI-743 is a type of CoEnzyme Q10, which is found naturally in our cells and is essential for proper energy production within the mitochondria. EPI-743 works like CoEnzyme Q10, as an antioxidant, carrying electrons along the energy chain to make energy in the form of ATP. EPI-743 is reported to be more potent and more highly absorbed than naturally occurring CoEnzyme Q10. The FDA granted Orphan Drug status to EPI-743 for the treatment of Leigh syndrome in June 2014.

EPI-589

EPI-589, also known as (R)-troloxamide Quinone, is claimed to have significant effects on modifying Glutathione (GSH) levels. GSH is found in nearly all cells and plays an important role, together with other antioxidants, in maintaining the effective clearing of free radicals.  

Clinical Studies

Friedreich’s ataxia - A Phase 2B Double-Blind, Placebo-Controlled, Clinical Trial of EPI-743 in Friedreich’s Ataxia

Leigh syndrome - A Phase 2B Randomized, Placebo-Controlled, Double-Blind Clinical Trial of EPI-743 in Children with Leigh Syndrome

Rett syndrome - A Placebo Controlled Trial of EPI-743 on Children with Rett Syndrome

Cobalamin C defect - A Placebo Controlled Trial of EPI-743 on Neurologic and Visual Function in Patients with Cobalamin C Defect

NIH Undiagnosed Diseases of Redox and Metabolism - A Placebo Controlled Trial of EPI-743 on Diseases of Mitochondrial or Metabolic Defects

MELAS - Safety and Efficacy of EPI-743 in Patients with MELAS

Parkinson’s disease - Effects of EPI-743 on Visual and Neurological Function in Patients with Parkinson’s Disease

ALS - A Phase 2A Safety and Biomarker Study of EPI-589 in Subjects With Amyotrophic Lateral Sclerosis

Edison Pharmaceuticals believes unraveling the science of mitochondrial disease holds promise for treating a family of devastating diseases. By gaining insight into the basic underpinninings of how our bodies make and regulate energy metabolism, Edison believes that the emerging field of mitochondrial medicines will provide key insights into the biology of aging.

Stealth Biotherapeutics is one of a new group of pharmaceutical companies developing drug treatments for genetic mitochondrial disease and acquired mitochondrial dysfunction, including heart failure, diabetic macular edema, certain skeletal muscle disorders, and rare inherited diseases such as Leber’s Hereditary Optic Neuropathy (LHON).

Treating Mitochondrial Dysfunction

Mitochondrial disorders are believed to arise either as a result of inherited genetic defects or through damage caused by a variety of common diseases. In either case, the result is the creation of oxidative stress and reduced energy production. Dysfunctional mitochondria are a key element in a variety of serious, debilitating diseases, both rare and common, such as:  

• Heart failure
• Age-related macular degeneration
• Kidney disease
• Cardiovascular and metabolic diseases
• Diabetic macular edema and retinopathies
• Neurodegeneration
• Certain skeletal muscle disorders

Stealth's Drug Pipeline

Bendavia - As of January 2016, Stealth received Fast Track designation by the FDA for its leading drug candidate, Bendavia, for the treatment of primary mitochondrial myopathy. Stealth markets Bendavia as an investigational drug with the potential to modify disease by preserving energetics and restoring normal energy production in mitochondria, while decreasing oxidative stress. According to Stealth, Bendavia penetrates the cellular and outer mitochondrial membranes, and targets cardiolipin, which is found exclusively in the inner mitochondrial membrane. Bendavia has been shown to positively impact dysfunctional mitochondria in nonclinical studies, with no effect in healthy mitochondria.

Ocuvia - In nonclinical studies, Ocuvia has demonstrated the potential to be the first investigational topical ophthalmic formulation to treat back-of-eye diseases, offering a an alternative to treatments that require physician-administered ocular injections. Ocuvia is designed to treat the underlying defects in mitochondria associated with diseases such as Diabetic Macular Edema, genetic Mitochondrial Optic Neuropathies and Age-related Macular Degeneration. These defects include excessive oxidative stress and decreased energy supply to affected cells of the eye, particularly in the retina. Ocuvia is currently in clinical studies for patients with Diabetic Macular Edema. Plans are also in development for Ocuvia to be studied in Mitochondrial Optic Neuropathies including Leber’s Hereditary Optic Neuropathy (LHON).

Clinical Studies

Ophthalmology

• ReVIEW Diabetic Macular Edema A dose-escalation study to evaluate the safety, tolerability and efficacy of Ocuvia to treat patients with diabetic macular edema (DME) and dry age-related macular degeneration (AMD)
• ReSIGHT Mitochondrial Optic Neuropathies – Leber’s Hereditary Optic Neuropathy A study to evaluate the safety, tolerability and efficacy of Ocuvia to treat patients with Leber’s Hereditary Optic Neuropathy (LHON)

Skeletal Muscle Diseases

• MOTION for Skeletal Muscle Disorders - A randomized, double-blind, placebo-controlled study to evaluate Bendavia on skeletal muscle function in the elderly

• MMPOWER for Mitochondrial Myopathy - A double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of Bendavia to treat myopathy in patients with genetically-confirmed mitochondrial disease

Cardio-renal Diseases

• PREVIEW for Heart Failure - A double-blind, placebo-controlled study to evaluate safety, tolerability and efficacy of Bendavia to treat heart failure patients

• EVOLVE for Acute Kidney Injury - A double-blind, placebo-controlled study to evaluate safety, tolerability and efficacy of Bendavia in chronic kidney disease (CKD) patients at risk of acute kidney injury (AKI)

Currently, there are no FDA-approved treatments for any orphan mitochondrial disease. This represents a significant unmet need for medicines that can restore mitochondrial function and work by improving energy supply at the cellular level. Stealth Biotherapeutics is focused on developing innovative treatments that can meet these needs.

You’ve heard it said many times before…you are what you eat! Consuming a diet high in fiber, vitamins, minerals, and antioxidants is enormously important to supporting the health of your mitochondria.

Healthy foods usually have lots of colors. Think carrots, butternut squash, kale, purple potatoes, and berries. These foods contain the highest amount of antioxidant nutrients that are important to supporting mitochondrial function.

When it comes to protein, try to consume some protein with every meal. Nuts, beans, low-fat dairy products, egg whites, and lean meats are the best sources of this vital nutrient. Low-fat, low-sugar yogurt is another great way to provide your body with protein, calcium, and healthy bacteria that also supports gut and immune system health.

K-PAX Protein Blend Immune Booster contains 10 grams of brown rice protein plus the same formula of mitochondrial support nutrients found in K-PAX Immune formula. It's the perfect way to get protein and a multivitamin in a flavorful, refreshing, and convenient drink. Learn More

The importance of this next recommendation cannot be overstated. Try to avoid consuming large amounts of sugar and processed foods. Processed sugars and carbohydrates are toxic to your body. They stress your pancreas, raise insulin levels, depress the health of your immune system, worsen cardiovascular disease and promote the growth of unhealthy bacteria in your gut.

You’ve probably heard the terms “good carbs” and “bad carbs”. Distinguishing between these two forms of carbohydrates is actually pretty straightforward. “Good carbs” are carbohydrates found in the bulk and produce sections of the grocery store. These include fruits, vegetables, brown rice, barley, quinoa, and all varieties of beans.

“Bad carbs” are carbohydrates that have been processed in a factory. Once carbohydrates go through a factory, they almost always have chemicals and preservatives added. They are also processed to the point where their nutritional value becomes significantly degraded.

Eating a healthy, natural foods diet is the foundation of good mitochondrial health!

Researchers at McGill University in Canada have discovered a connection between peripheral neuropathy (nerve damage) and mitochondrial dysfunction. The findings, entitled, “Mitochondrial and bioenergetics dysfunction in trauma-induced painful peripheral neuropathy” were published in the September issue of Molecular Pain.

Peripheral neuropathy causes pain, numbness, weakness, and loss of sensation in the extremities of the body. The nerves affected by peripheral neuropathy send information from your central nervous system (brain and spinal cord) to the rest of your body. Damage to these nerves can occur from diabetes, chemotherapy, HIV, and trauma.

Mitochondria dysfunction can impair cellular energy metabolism and affect nerve cells which potentially leads to cell death and neurodegeneration. The lack of energy can trigger the spontaneous activity of sensory nerve cells resulting in neuropathic pain.

In this study, researchers demonstrated that trauma-induced peripheral neuropathy causes a persistent dysfunction of the mitochondria and suggest that therapeutic agents that seek to normalize mitochondrial dysfunction could benefit pain treatment.