Therapies for Rare Mitochondrial Diseases Begin to See Traction

Transmition Electron microscopy of an epithelial c

Transmition Electron microscopy of an epithelial c

Dlumen/Getty Images/iStockphoto

The approval of Reata Pharmaceuticals’ Skyclarys for Friedreich’s ataxia highlights progress being made in the treatment of rare mitochondrial diseases.

Transmition Electron microscopy of an epithelial cell showing mitochondria/courtesy of Dlumen/iStock

They’re the powerhouses of the cell, generating energy for nearly every organ in the body. But when mitochondria are dysfunctional, the resulting power outage can cause devastation for children and adults with rare and ultra-rare diseases. One rare mitochondrial disease, Friedreich’s ataxia, saw its first approval in March when the FDA greenlit Reata Pharmaceuticals’ Skyclarys for adults and adolescents 16 and older.

While this bodes well for adult diseases, there have not been many recent advances in treating pediatric mitochondrial diseases, said Jan Smeitink, CEO of Khondrion, a company developing symptomatic treatments for mitochondrial diseases.

“The good thing is that, at least now, there is this huge interest in primary mitochondrial diseases, so more companies are working in the space,” he told BioSpace. “It’s also good to notice that different companies have compounds working on different targets.”

Jan Smeitink

Jan Smeitink

A Glimmer of Hope in Pearson Syndrome

One of these companies is Israel-based Minovia Therapeutics, which is developing a mitochondrial cell therapy for Pearson syndrome, a multisystem disease caused by single, large deletions in mitochondrial DNA (mtDNA).

The mitochondria are the only place in the cell where there is DNA outside of the nucleus, Natalie Yivgi-Ohana, co-founder and CEO of Minovia, told BioSpace. This makes the organelle particularly vulnerable. “It’s exposed. It’s circular. It has no protections, no proofreading, so mutations just accumulate with time.”

Pearson syndrome affects fewer than 1,000 people in the U.S., according to the Genetic and Rare Diseases Information Center.

“Almost 50% of [patients] will die before the age of five, and the rest will just develop a multisystemic, terrible disease that affects almost every organ system,” Yivgi-Ohana elaborated. Patients experience neurodegeneration, muscular dysfunction, cardiac dysfunction and diabetes. “It’s almost like the whole body is collapsing.”

Minovia’s Mitochondrial Augmentation Technology (MAT) platform involves extracting a patient’s hematopoietic stem cells, enriching them with healthy mitochondria from a donor and then infusing them back into the body. This allows the cell’s natural processes to select for the healthy versions of the organelles, Yivgi-Ohana said.

Pearson syndrome is the only mitochondrial disease where bone marrow failure occurs, so “hematopoietic stem cells are very relevant to treat at least the hematopoietic environment of that patient,” Yivgi-Ohana said. Generally, mitochondria—and consequently—mtDNA, is inherited only from the mother. But Pearson is usually caused by de novo mutations, enabling the mother to serve as a donor, she said.

Natalie Yivgi-Ohana

Natalie Yivgi-Ohana

In a compassionate use study, seven young patients—four with Pearson syndrome and two with another primary mitochondrial disease, Kearns-Sayre syndrome (KSS)—were treated with MAT (MNV-101). Prior to treatment, all patients had potentially life-threatening symptoms, including advanced multi-organ disease, according to Minovia.

Minovia extracted one unit of blood from the donor, isolated the mitochondria from the white blood cells and introduced them into the patient’s hematopoietic stem cells in the lab before re-injecting those into the patient. Treatment with MNV-101 was well-tolerated and resulted in normal mitochondrial DNA in the blood of four patients, which Minovia said indicated a reduction of mitochondria containing the disease-causing deletions.

“The first few patients showed remarkable improvement and reversal of the disease,” Yivgi-Ohana said. She shared the story of a six-and-a-half-year-old boy who was confined to a baby stroller due to stunted growth, muscle weakness and fatigue. After treatment with MAT, “the first thing that we observed in this patient was a burst of energy in the waking hours of the day,” Yivgi-Ohana said. The baby stroller disappeared and the child started to walk and run.

The boy continued to improve, and his kidney function stabilized for four years after treatment before beginning to deteriorate in the past two years, Yivgi-Ohana said. Based on this patient and eleven others who have been treated with MAT, she believes another dose of MNV-101 will be required.

Leigh Syndrome and MELAS Spectrum Disorders

Waltham, Mass.–based IMEL Biotherapeutics aims to restore mitochondrial function with cell-based therapies to treat both genetic and age-related diseases. On the genetic side, IMEL is targeting Leigh syndrome, a severe neurometabolic disorder that affects children carrying certain mutations in their mtDNA.

The company’s Mitochondrial Replaced Cells (MirC) technology allows it to deplete the dysfunctional mitochondria and replace them with healthy mitochondria, Silvia Noiman, founder, chair and CEO of IMEL, told BioSpace.

Silvia Noiman

Silvia Noiman

IMEL is currently testing the MirC process in animal models resembling Leigh syndrome. Using the MirC process in stem cells and T cells from both animal models and healthy humans, IMEL has shown that it can replace almost 90% of the host cells’ dysfunctional mitochondria with functional organelles, Noiman said. She believes the technology “can be a game changer.”

Noiman will expound on the age-related impacts of mitochondrial disorders at the Biomed Israel Conference, held this week in Tel Aviv.

Mitochondrial disorders affect adults too. Khondrion has several therapies in development for these diseases. Its most advanced product is sonlicromanol for the treatment of cognitive dysfunction in adults with MELAS spectrum disorders. Classical MELAS spectrum disorders, including maternally inherited diabetes and deafness (MIDD) and mixed phenotypes, are most often caused by a mutation in the MT-TL1 gene in the mtDNA. The most oft-affected organs are the brain, muscles and pancreas, Smeitink said.

Between Phase IIb and open-label extension studies, Smeitink said the company has good safety data for up to 78 weeks. Khondrion is currently discussing Phase III trial design with the FDA and European Medicines Agency.

Sonlicromanol, a reductive and oxidative distress modulator with anti-inflammatory properties, aims to correct the outward manifestations of mutations in the cell lines of patients with mitochondrial diseases. Khondrion is also testing the drug for the treatment of mitochondria-based movement disorders in children.

The Path Forward

The mitochondrial disease space comprises approximately 300 neuro-metabolic genetic disorders, according to Khondrion.

“The problem with mitochondrial diseases is that it’s not one disease. It’s hundreds and hundreds of diseases,” Mary Kay Koenig, pediatric neurologist and director of the Mitochondrial Center of Excellence at UTHealth Houston, told BioSpace. Gene replacement therapies and DNA modifications are focused on a very small proportion of the diseases, she said.

For Smeitink, small molecule therapies are “the way to go” in treating mitochondrial diseases, at least for the next 10 years. He said gene and cell therapy also hold promise but “need a little bit more time as several obstacles first have to be overcome.” He pointed to vector design, targeted tissue tropism and efficient delivery, transgene expression and immunotoxicity.

Yivgi-Ohana said that autologous hematopoietic stem cells are the most trusted cell therapy. She said that the riskiest part of such treatment is typically the preconditioning—clearing the bone marrow with chemotherapy to allow engraftment of cells in the bone marrow niche—but added that this is not done for Pearson patients because their bone marrow has low cellular content, meaning there is space in the bone marrow niche for engraftment of the augmented cells.

Another primary challenge is phenotyping, Koenig said. “You can’t really find a treatment for something if you don’t understand what the natural history of it is, and I think . . . we’re still in the process of trying to understand [mitochondrial] diseases,” she said. “It makes it really hard to determine whether or not a drug is efficacious if you don’t know what’s supposed to happen to the patient” in the natural course of the disease.

One initiative, The Leigh Syndrome Roadmap Project: A Natural History Study, is trying to address this challenge. The project, being run out of the Children’s Hospital of Philadelphia, aims to better understand the natural history of Leigh syndrome and determine proper endpoints for clinical trials, Koenig said.

Currently, there are not many ongoing studies in mitochondrial diseases for children, Smeitink noted. While there are around 200 active trials for mitochondrial diseases listed on as of May 2023, just 10 of these are for Leigh’s syndrome and two are for Pearson syndrome. “That is unfortunate,” he said. “But it will change, I’m sure.”

Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at Follow her on LinkedIn: and Twitter: @chicat08.

The Biomed Israel conference paid for Heather McKenzie to travel to Israel to meet with Minovia Therapeutics in December 2022.

Heather McKenzie is a senior editor at BioSpace. You can reach her at Also follow her on LinkedIn.