Kearns-Sayre Syndrome

Researchers found that altered B cell function in children with mitochondrial disorders led to a weaker and less diverse antibody response to viral infections. Researchers analyzed gene activity of immune cells in children with mitochondrial disorders and found that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress. In a new study, National Institutes of Health (NIH) researchers found that altered B cell function in children with mitochondrial disorders led to a weaker and less diverse antibody response to viral infections. The study, published in Frontiers in Immunology was led by researchers at the National Human Genome Research Institute (NHGRI), who analyzed gene activity of immune cells in children with mitochondrial disorders and found that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress. "Our work is one of the first examples to study how B cells are affected in mitochondrial disease by looking at human patients," said Eliza Gordon-Lipkin, M.D., assistant research physician in NHGRI's Metabolism, Infection and Immunity Section and co-first author of the paper. Mitochondria are important components of nearly every cell in the body because they convert food and oxygen into energy. Genomic variants in more than 350 genes have been linked to mitochondrial disorders with varied symptoms depending on which cells are affected. "For children with mitochondrial disorders, infections can be life threatening or they can worsen the progression of their disorder," said Peter McGuire, M.B.B.Ch, NHGRI investigator, head of the Metabolism, Infection and Immunity Section and senior author of the study. "We wanted to understand how immune cells differ in these patients and how that influences their response to infections." Around 1 in 5,000 people worldwide have a mitochondrial disorder. Examples of mitochondrial disorders are Leigh's syndrome, which primarily affects the nervous system, and Kearns-Sayre syndrome, which primarily affects the eyes and heart. While mitochondrial disorders are known to affect organs such as the heart, liver, and brain, less is known how they affect the immune system. Using a genomic technique called single-cell RNA sequencing, which analyzes gene activity in different cell types, researchers studied immune cells found in blood. These cells include different types of white blood cells that help the body fight infections. During stressful conditions, these cells produce a microRNA called mir4485. MicroRNAs are small strings of RNA that help control when and where genes are turned on and off. mir4485 controls cellular pathways that help cells survive. "We think that B cells in these patients undergo cellular stress when they turn into plasma cells and produce antibodies, and these B cells then try to survive by producing the microRNA to cope," said Dr. McGuire. "But the B cells are too fragile due to their limited energy, so they are unable to survive the stressful conditions." Researchers used a technique called VirScan to look at all past viral infections, assess how well the immune system fought those infections and see the effects of B cells and plasma cells on antibody production. With a weaker antibody response, the immune systems in children with mitochondrial disorders are less able to recognize and neutralize invading viruses and clear infections. Researchers aim to use the results of this study to guide future treatment of patients with mitochondrial disorders, noting that more translational studies are needed in this research area.

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 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 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 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 ClinicalTrials.gov 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 heather.mckenzie@biospace.com. 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.

First in human clinical study provides proof-of-concept for mitochondrial augmentation therapy platform, which enables use of healthy mitochondria to improve mitochondrial function and mitigate effects of large-scale mitochondrial DNA (mtDNA) deletion syndromes Study showed improved quality of life measures in children with Pearson Syndrome and Kearns-Sayre Syndrome spectrum No treatment-related adverse effects reported in study WOBURN, Mass. and HAIFA, Israel, Dec. 21, 2022 (GLOBE NEWSWIRE) -- Minovia Therapeutics, a clinical-stage global biotechnology company, today announced that the findings of the first clinical use of mitochondrial augmentation therapy (MAT) platform to treat pediatric patients with primary mitochondrial diseases have been published in Science Translational Medicine. The study was conducted in collaboration with global leaders in the field of hematology and primary mitochondrial disease at Sheba Medical Center (Tel Hashomer, Israel). Single, large deletions in mitochondrial DNA (mtDNA) can lead to a variety of devastating diseases, including Pearson Syndrome and Kearns-Sayre Syndrome (KSS). These mtDNA deletion syndromes are sporadic, uncurable and ultimately fatal. Pearson syndrome is a bone marrow failure disease that usually begins in infancy. In addition to presenting with sideroblastic anemia, patients are characterized by exocrine pancreas dysfunction. About half of patients die in infancy or childhood, while many who survive go on to develop KSS, a progressive multisystem disorder. “These findings demonstrate that mitochondrial augmentation therapy is feasible in children with mitochondrial DNA deletion syndromes and that autologous CD34+ cells augmented with mitochondria derived from maternal blood may potentially deliver some functional improvement for patients living with these debilitating diseases for which there are no available therapies,” said Elad Jacoby, M.D., Ph.D., Hemato-oncology Pediatric department, Sheba Medical Center. MAT is designed to rescue mitochondrial function and metabolic activity in diseased cells through enrichment with healthy mitochondria. This builds upon Minovia’s previous demonstration that MAT provides long-term functional benefit in an immunocompromised mouse model, and that mitochondria can transfer between hematopoietic stem cells (HSCs) in vivo (Jacoby et al 2021). Preclinical studies showed that hematopoietic stem and progenitor cells (HSPCs) can transfer normal mitochondria to hematopoietic and non-hematopoietic cells and improve disease features (Rocca et al., 2017). Minovia is developing MAT to treat Primary Mitochondrial Diseases such as Pearson syndrome, as well as other mitochondrially-related sideroblastic anemias. The Company’s lead investigational candidate, MNV-101 (MNV-BM-BLD), has been granted the Fast-Track, Orphan Drug and Rare Pediatric Disease designations by the U.S. Food and Drug Administration. The latest study reported results from six patients ranging from 2 to 7 years of age: four with Pearson syndrome and two with KSS spectrum. All six patients suffered from significant failure to thrive and advanced multi-organ disease, which was either immediately or potentially life-threatening, requiring multiple ongoing supportive care interventions. Key Findings No treatment-related adverse events were reported. Adverse events related to the leukapheresis procedure were managed with standard medical care. Adverse events that occurred following treatment were expected due to the patient’s underlying disease and resolved spontaneously or with appropriate treatment. Higher levels of normal mitochondrial DNA were observed in the blood of four out of six patients, indicating a reduction of mitochondria with large DNA deletions. Clinical improvement in aerobic function was observed in some patients, and five of six patients experienced weight gain. Quality of life measurements showed improvement in most patients. Changes in the general well-being of children and physical activity were reported, along with increased time spent awake and in play. A series of aerobic and endurance tests were performed on two patients. Both patients demonstrated improvement in leg muscle strength and endurance at 6 and 12 months post treatment. One patient, who at baseline was unable to walk any distance, was able to walk 10 meters at 12 months and had improvement on the 30-second sit-to-stand test. Another patient demonstrated improvement in muscle function in some tests and a sustained improvement in others, including the six-minute walk test and sit-to-stand capacity at 6 and 12 months. “We are tremendously encouraged by evidence of improvement to the quality of life and well-being of the children treated with MAT, including clinical improvements in aerobic function, weight gain and increased strength and endurance," said Natalie Yivgi Ohana, Ph.D., co-founder and CEO of Minovia. "We believe these findings lay important groundwork for further development of MAT and future clinical trials to demonstrate the effectiveness and safety of MAT in patients with primary mitochondrial disorders and other diseases. Our excellent collaboration with the clinicians and teams at the Sheba Medical Center, as well as with patient advocacy groups, will enable us to accelerate the clinical development plans for Pearson Syndrome patients." About Primary Mitochondrial Diseases (PMD) and Mitochondrial Dysfunction Primary Mitochondrial Diseases (PMDs) are chronic, genetic disorders that occur when mitochondria fail to produce enough energy for the body to function properly. Mitochondrial diseases affect about one in 5,000 people globally and can be sporadic or inherited and onset can occur at any age. Mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas. Mitochondrial dysfunction also plays an important role in more prevalent diseases, such as Alzheimer’s disease, muscular dystrophy, amyotrophic lateral sclerosis and diabetes. About Minovia Minovia Therapeutics is a clinical-stage global biotechnology company committed to the discovery and development of novel approaches to treating diseases caused by mitochondrial dysfunction. Minovia’s Mitochondrial Augmentation Therapy (MAT) platform is designed to extend and enhance human lives by restoring mitochondrial function using autologous stem cells enriched with healthy, functional mitochondria. This unique approach capitalizes on the natural ability of mitochondria to transfer between cells. The company’s initial clinical focus is on primary mitochondrial diseases, such as Pearson syndrome, a fatal pediatric disease, and hematological disorders that include mitochondrial dysfunction. Minovia was founded by leading researchers in mitochondrial biology and is headquartered in Haifa, Israel, with operations in Massachusetts. For more information, visit . Contact: info@minoviatx.com Phone: +972-747033354