Drug Repurposing for Leigh Syndrome

What is drug repurposing for Leigh syndrome?

Simply put, it’s identifying existing drugs that have already been approved to treat other diseases, which may have the potential to be applied to Leigh syndrome or mitochondrial disease. 

Why devote resources to repurposing drugs for Leigh syndrome and mitochondrial disease?

• Saving time and money: Development of a brand-new drug from discovery to approval can take on average 10 to 15 years or more, and cost millions or billions (in US dollars). When the disease affects a very small proportion of the world’s population, it’s even more difficult for government funders and companies to invest. 

• Shared biology: Different diseases can share common biological pathways and symptoms that stem from the same kinds of stress to cells and organs. A drug developed for cancer, epilepsy, inflammation, or metabolism could unexpectedly hit the right target and offer some hope or some relief. 

• Speed and safety: Furthermore, repurposed drugs have often already been tested in humans, and might have known safety information and side effects, allowing quicker transition into small studies or allowance for uses that are “off-label” (meaning not yet approved). Repurposing lowers development costs, making it more feasible for academic researchers and small companies to push therapies forward. 

• Community impact: Because of the lower risk and cost, nonprofit funding from organizations like Cure Mito can have a greater impact. In a fast-moving disease that impacts children, parents, doctors, and foundations can band together and push hard to empower patient-driven science.

How do researchers find and study repurposed drugs?

Drug repurposing can involve many different approaches that apply different computational methods, laboratory techniques, and animal models, separately or in parallel. Some ways to approach it include:

Identifying potential drugs

• Comparing what we know about the overlap between Leigh syndrome and other treatable conditions, to see whether existing medicines target the same biological problem
• Using computers or AI to scan huge amounts of data from drug chemistry or human biology to find existing drugs that act on relevant pathways

Screening existing drugs

• Testing thousands of existing drugs on Leigh syndrome patient cells to see which ones actually help sick cells to survive or grow better 
• Trying approved drugs in very simple organisms (like yeast) to see whether they improve disease biology or extend life
• Building advanced computational models using real Leigh syndrome patient data to simulate how thousands of drugs might impact each unique individual 

Real-world evidence

• Learning from the experience of doctors, when a medication given for a different reason appears to help children with the disease
• Studying patterns in patient registries to see whether children who happen to be taking certain medications do better over time than those who aren’t.

What are the steps needed to get a repurposed drug approved for Leigh syndrome?

At a high level, this follows the same path as a new drug but it is usually much shorter and cheaper. First, researchers need to provide “pre-clinical” evidence, such as showing the overlap in biology between Leigh syndrome and the disease the drug was developed for. Then, they need data from cells, animals, or human tissues, that shows promise for the drug to improve Leigh syndrome biology or symptoms. 

Next, the researchers have to prepare and submit an Investigational New Drug (IND) application to agencies like the FDA or EMA. Then clinical trials can proceed, but they can usually skip some early safety steps and focus on whether the drug improves symptoms and is safe for patients with Leigh syndrome. Finally, if the data shows a benefit, the drug’s intended use, known as its indication, can be expanded to include Leigh syndrome. 

Do we still need a clinical trial to use a repurposed drug? 

Yes, almost always. Even if a drug is already approved, it was approved for a specific purpose, dose, and disease. To use a repurposed drug for Leigh syndrome, regulators (like the FDA in the US or EMA in Europe) want evidence that it works and is safe in people with Leigh syndrome and is being used at the right dose with the right timing. A drug that’s safe in middle-aged men might behave differently in children with a rare disease.    

How does this differ from a traditional “new drug” clinical trial?

Finding Leigh Syndrome drug candidates using yeast models

One way Cure Mito is funding drug repurposing studies is by partnering with Perlara, a biotechnology company focused on rare disease therapeutics. They specialize in drug repurposing for rare genetic diseases, from working with models and screening tools to providing support for the early steps towards clinical trials. Perlara facilitated the testing of thousands of existing drugs in yeast that have been engineered without the SURF1 gene, meaning that they mimic aspects of Leigh syndrome. This approach identified losmapimod, a drug originally developed for a muscle disease, as a promising candidate. 

Losmapimod received a special status called Rare Pediatric Disease Designation (RPDD) from the US FDA, a special status that helps to speed and incentivize the pursuit of treatments for rare childhood diseases. Cure Mito continues to collaborate with Perlara and is helping to move this work towards testing in very small clinical trials of two patients with Leigh syndrome, one with an ECHS1 mutation and one with a SURF1 mutation.

Advanced brain models and AI

Cure Mito has also funded cutting-edge work on drug repurposing using human neurons and lab-grown models of the brain called organoids. In Alessandro Prigione’s lab at Heinrich Heine University in Dusseldorf, Germany (and collaborating institutions), researchers combined machine learning, genetic analysis, and drug screening to identify existing compounds that could reverse disease-related changes in these models of Leigh syndrome. 

This work highlighted two promising paths. The first was azole compounds (antifungals), which improved brain development features in SURF1 models, from yeast to brain organoids. These compounds have so far been used mainly only topically in humans. Strategies are being explored on how to move these drugs forward for systemic use in patients, by first testing them in mice and pigs with Leigh syndrome mutations.

A second promising compound identified in these screens was sildenafil, a drug originally developed to improve blood flow. Sildenafil boosted neuron growth and extended survival in mouse and pig models. In addition, a small, exploratory treatment study of sildenafil was carried out in six individuals with MT-ATP6 Leigh syndrome, who showed modest improvements in movement and metabolism. Based on these results, sildenafil has received Orphan Drug Designation from the European Medicines Agency (EMA), a status that incentivizes the development of drugs for rare diseases. 

A larger clinical study is now being planned across several European sites in people with Leigh-like symptoms who carry MT-ATP6 variants. This study will compare sildenafil to a placebo to better understand how safe the drug is and whether it may help patients. The trial is supported by funding from the European Commission through the Horizon Consortium SIMPATHIC. In addition, a separate grant from the European Rare Diseases Research Alliance (SynLeigh) will allow the Prigione lab and collaborators to explore whether sildenafil, alone or in combination with other drugs, could benefit people with different forms of Leigh syndrome. 

Using Leigh syndrome patient RNA to guide drug discovery

Cure Mito also enabled families around the world to participate directly in drug repurposing research from home. Through a partnership with Unravel Biosciences, patients (and healthy siblings or family members) were able to use a nasal swab kit that allowed scientists to collect their RNA. A powerful research tool called RNA sequencing (RNAseq) can be applied to study how RNA expression is behaving differently in Leigh syndrome. Unravel built AI-driven computational tools to detect disease patterns and predict which existing drugs might benefit specific patients. They created “Living Molecular Twins™,” which are digital simulations of individual patients, and used them to screen 40,000 molecules, including approved drugs and supplements. 

Around a dozen top scoring repurposable candidates have been selected for additional screening. Among the top hits were the same antifungal drugs identified using patient cell screening by the Prigione lab. The results also suggests that, despite the many causes of Leigh syndrome, patients may fall into 2-3 subgroups based on how they are predicted to respond to treatments. This insight could help streamline and speed the development of therapies that work across multiple genetic forms of the disorder.

Right now Unravel’s efforts are focused on Leigh syndrome caused by the genes SURF1 and ECHS1 (found in the nucleus or “control center” of cells), as well as MT-ATP6 and MT-ND1 (found in the mitochondria or cell “batteries”). There are plans in place to expand these efforts to additional genes. Unravel has identified many candidate drugs that could potentially be explored for the treatment of Leigh syndrome, and Cure Mito makes the resulting patient and control RNA data available to researchers who want to explore these findings further. 

Testing approved drugs in Leigh Syndrome patient-derived brain cells

Another strategy that Cure Mito supports involves turning small skin samples donated by Leigh syndrome patients into brain cells in the lab, allowing researchers to study the disease and test potential treatments. In collaboration with Transcripta Bio, Cure Mito enabled screening of thousands of FDA-approved drugs in neurons derived from Leigh syndrome patients. 

This work identified drug candidates that improved the function of mitochondria in cells. In particular, they saw promising results for a drug called omaveloxolone that was developed for a brain disease called Friedreich’s Ataxia. This led to a very tiny clinical trial (n=1) of omaveloxolone in one patient with SURF-1 Leigh syndrome. 

These studies also produced long-lasting cell models made from a patient and an unaffected family member. The cell lines are stored at the Coriell Institute for Medical Research and can be shared with other scientists, allowing many teams to continue studying Leigh syndrome without needing to collect new patient samples. 

Further Reading

A February 2026 paper published in Cell describes the latest findings from patient-derived cell models and preclinical studies identifying sildenafil as a promising candidate to improve mitochondrial function and disease outcomes in Leigh syndrome. An article on this is also published by NY Post.

In a May 2023 blog post, Perlara CEO, Dr. Ethan Perslstein, describes the completion of a big step of the SURF1 Leigh syndrome screen:

A May 2024 paper describes a clinical trial of losmapimod for a muscle disease. 

Studies published in 2018 and 2022 are about the methods that Transcripta Bio is using for drug discovery.

A 2024 publication discusses computer-based drug screening and machine learning in brain organoids and yeast to identify repurposable drugs for SURF1 defects.

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