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Home » Rare diseases » How far are we from being able to treat mitochondrial disorders?

This page has been funded by UCB, but editorial control lies with the contributors. UCB only performed a medical accuracy review but was not otherwise involved in the content.

Caterina Garone MD, PhD

Associate Professor Medical Genetics, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna; Child Neurology Consultant, IRCCS Institute of Neurological Sciences, Child Neuropsychiatry Unit, Bologna, Italy

Mitochondrial disorders are a group of rare diseases that affect 1 in 5,000 live births. They can present at any age and have a drastic impact on any organ and tissue.

Mitochondria — which provide ‘the battery charge’ for practically every cell in our bodies — are vital for our survival. “They are the powerhouse responsible for converting nutrients into energy,” explains Dr Caterina Garone, Associate Professor Medical Genetics, Department of Medical and Surgical Sciences. “When mitochondria are not working properly, it’s as though a light in the affected organs and tissues has been turned off.” 

Inherited and unpredictable mitochondrial disorders 

While mitochondrial disorders are extremely rare — affecting just 1 in 5,000 live births — they can be devastating and, in some cases, life-threatening. Caused by genetic mutations, they are either inherited from the mother when a defect is in the mitochondrial DNA or inherited from one or both parents when the defect is in the nuclear DNA.  

Onset occurs at any age and can be found in any part of the body — from the brain, nerves, pancreas and heart to kidneys, liver, muscles, eyes and ears. These disorders are also unpredictable and may affect just one tissue or organ, or multiple tissues and organs. They are currently incurable. 

Getting a diagnosis of mitochondrial disorder 

Even diagnosis is a challenge. “Unfortunately, because symptoms are so varied and similar to other diseases, mitochondrial disorders can be difficult to diagnose,” says Dr Garone. “Patients can present with weakness, delay in acquiring or loss of motor milestones, seizure, cardiomyopathy, liver dysfunctions, kidney failure, anaemia and gastrointestinal symptoms.”  

If a mitochondrial disorder is suspected, patients will undergo clinical observation, metabolic tests and an analysis of muscle biopsy. However, a definitive diagnosis is obtained by genetic testing. 

The main barrier is moving
treatment from bench to bedside.

Studying mitochondrial depletion syndrome 

Several novel therapies for mitochondrial disorders are currently undergoing research studies, but very few are reaching patients with clinical trials. Nevertheless, Dr Garone believes that the treatment landscape is changing. For example, her clinical and research lab focuses on a subgroup of disorders called mitochondrial depletion syndrome, where cells lack multiple copies of mitochondrial DNA, causing severe dysfunction of the enzymes responsible for energy production.  

Dr Garone has specifically worked on a disease called thymidine kinase 2 (TK2) deficiency, which, in infants, can lead to early death. If onset begins in childhood, it can result in severe weakness and loss of acquired milestones while onset in adults can result in milder symptoms. “Thymidine kinase 2 is likely to be an underestimated condition because the spectrum of the disease is so varied and clinical symptoms can mimic other neuromuscular disorders,” she explains. 

Cutting-edge research opens up opportunities for new treatments

Still, there is hope. Through disease models and clinical trials, Dr Garone has demonstrated that a therapy known as nucleoside supplementation therapy can be effective in preventing TK2 disease progression during clinical trials. “When the treatment is started early in life, it can prevent the manifestations of symptoms,” she says. “An early diagnosis, even with a neonatal screening, is important to immediately start the treatment and cure patients.” There is a regulatory hurdle to clear: nucleoside treatment is waiting for FDA approval and is currently only available under controlled clinical trials or early-access compassionate use. 

“The main barrier is moving treatment from bench to bedside,” agrees Dr Garone. “For example, gene therapy for mitochondrial disorders is an exciting research area, although, additional studies are needed before translation to humans. However, finding funding for a clinical trial in the rare disease space can be challenging because only a small number of patients are affected. Yet, these patients have devastating, life-threatening conditions that need to be treated. I believe that, in the next five years, several new molecules will become available, and these will make a difference.”  

This page has been funded by UCB, but editorial control lies with the contributors. UCB only performed a medical accuracy review but was not otherwise involved in the content.

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