BACKGROUND: Leigh syndrome is a rare, progressive neurometabolic disorder caused by pathogenic variants in over 110 mitochondrial or nuclear genes. Its clinical and genetic heterogeneity creates challenges for diagnosis, care, and research. Cure Mito Foundation, a parent-led nonprofit established in 2018 to develop a gene therapy for SURF1-related Leigh syndrome, has since evolved into a global organization supporting individuals and families worldwide affected by all forms of Leigh syndrome. METHODS: This article describes the multifaceted efforts of Cure Mito Foundation to accelerate research and support for Leigh syndrome through family-led engagement and collaborative scientific partnerships. Strategies include funding the development of diverse disease models, gene therapies, drug repurposing pipelines, and a global patient registry. Emphasis is placed on co-production with affected families, sharing of biospecimens and data, and alignment with regulatory and research standards. RESULTS: The Leigh Syndrome Global Patient Registry comprises over 400 participants from 48 countries, with data made available to qualified researchers, and results shared regularly with the patient community to promote transparency and trust. Notable research accomplishments of Cure Mito include facilitating the development of multiple gene therapy candidates, patient-derived organoids and animal models, and repurposed drugs now entering early-phase trials. Cure Mito also played a key role in the launch of the Mitochondrial and Inherited Metabolic Disease Taskforce, led by the Critical Path Institute (C-Path), to integrate registry and clinical data into the Rare Disease Cures Accelerator platform. Additional efforts include community-developed educational tools, international awareness campaigns, and support programs tailored to the unique needs of Leigh syndrome families. CONCLUSIONS: Through relentless effort and dedication, the Cure Mito Foundation has shown that a small group of determined individuals can drive extraordinary change. By building a global patient registry, advancing data sharing and research, developing patient-centric education and support, and facilitating collaboration among scientists, clinicians, and families, the Foundation has created momentum toward effective treatments. With support from the Chan Zuckerberg Initiative’s Rare As One grant, Cure Mito is poised to expand its impact even further.
Mitochondrial disease encompasses untreatable conditions affecting tissues with high energy demands. A severe manifestation of mitochondrial disease is Leigh syndrome (Leigh), which causes defects in basal ganglia and midbrain regions, psychomotor regression, lactic acidosis, and early death. We previously generated isogenic pairs of Leigh cerebral organoids and uncovered defects in neuromorphogenesis. Here, we leveraged on this disease feature to devise drug discovery pipelines. We developed a deep learning algorithm tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. In parallel, we performed a survival drug screen in yeast and validated the repurposable hits on branching capacity in Leigh neurons. The two approaches independently highlighted azole compounds, Talarozole and Sertaconazole, both of which lowered lactate release and improved neurogenesis and neurite organization in Leigh midbrain organoids. Hence, targeting neuromorphogenesis has led to identify potential new drugs for mitochondrial disease and could prove an effective strategy for further drug discovery. ### Competing Interest Statement The authors declare no competing financial or commercial interests. C.M., S.O., A.D.S., and A.P. filed a patent application for the use of Talarozole in mitochondrial diseases. C.M., K.W., E.P, and A.P. filed a patent application for the use of Sertaconazole in mitochondrial diseases.
Introduction: Leigh syndrome (LS) is a rare, severe neurometabolic disorder and a type of primary mitochondrial disease. The Cure Mito Foundation is a nonprofit foundation founded in 2018 by parents of affected children. The organization's mission is to unite the global LS community to accelerate patient-centered research, treatments, and cures. Cure Mito has launched a global patient registry for Leigh syndrome in September 2021 to better understand the disease, facilitate clinical trials recruitment, and build a strong global community. Objectives: Patient data is collected in registries for getting a real-world view of patient reported outcomes, and to improve the understanding of the disease. Establishment of interoperability of therapies. The project described here has been undertaken to establish such interoperability for Leigh syndrome patient registry data.Methods: Establishing interoperability consisted of assessment of all data elements and collected data, alignment of data elements and variables with CDASH domains and variables, terminology alignment, data transformation, and compliance assessment. Results: Data assessment has been done, domain map has been developed, and data has been converted to CDASH standard.Conclusion: Cure Mito Foundation and Sumptuous Data Sciences, LLC completed a project focused on interoperability of Leigh syndrome patient registry data with CDISC standards, converting the data to CDASH standards, with SDTM conversion in progress. This project is a key milestone for all stakeholders who collect real world data in rare diseases.
Abstract Background Patients with hereditary hemorrhagic telangiectasia (HHT) are at risk for organ vascular malformations including arteriovenous malformations (AVMs) in the brain and lungs. North American HHT Centers of Excellence (CoEs) routinely screen for brain and lung AVMs, with the primary goal of detecting AVMs which can be treated before complications arise. Current international HHT guidelines provide recommendations for initial screening for brain and lung AVMs among children and adults with the disease, but rescreening recommendations are not comprehensively addressed and have not been reported. We determined current rescreening practices for brain and lung AVMs for children and adults with HHT among North American HHT CoEs. Methods We surveyed North American HHT CoEs regarding rescreening practices for new brain and lung AVMs in children and adults with initial negative screening. Results All thirty CoEs responded; 28 regarding pediatric (93.3%) and 30 (100%) regarding adult HHT care. The median duration of practice experience in HHT was 11.5 (range 3–30) years for providers of pediatric HHT care and 11.5 (range 3–35) years for providers of adult HHT care. The median number of patients followed at each CoE was 60 for children (range 8–500) and 375 for adults (range 30–1500). 25/28 CoEs (89.3%) reported rescreening children for brain AVMs, most commonly with enhanced MRI (21/25, 84%). 25 CoEs rescreen children for lung AVMs, most commonly every 5 years (15/25). Only 4/30 CoEs (13.3%) rescreen adults for brain AVMs. 26/30 CoEs (86.7%) reported rescreening adults for lung AVMs, most commonly every 5 years (18/26, 69.2%). Conclusions Most HHT CoEs routinely rescreen children for brain and lung AVMs and adults for lung AVMs when initial screening is negative, but adults are infrequently rescreened for brain AVMs. Long-term data regarding risk for new brain and lung AVMs are required to establish practice guidelines for rescreening.
Background Leigh Syndrome (LS) is a rare genetic neurometabolic disorder, that leads to the degeneration of the central nervous system and subsequently, early death. LS can be caused by over 80 mutations in mitochondrial or nuclear DNA. Patient registries are important for many reasons, such as studying the natural history of the disease, improving the quality of care, and understanding the healthcare burden. For rare diseases, patient registries are significantly important as patient numbers are small, and funding is limited. Cure Mito Foundation started a global patient registry for LS in September 2021 to identify and learn about the LS patient population, facilitate clinical trial recruitment, and unite international patients and researchers. Priorities were to allow researchers and industry partners to access data at no cost through a clear and transparent process, active patient engagement, and sharing of results back to the community. Results Patient registry platform, survey design, data analysis process, and patient recruitment strategies are described. Reported results include demographics, diagnostic information, symptom history, loss of milestones, disease management, healthcare utilization, quality of life, and caregiver burden for 116 participants. Results show a high disease burden, but a relatively short time to diagnosis. Despite the challenges faced by families impacted by Leigh syndrome, participants, in general, are described as having a good quality of life and caregivers are overall resilient, while also reporting a significant amount of stress. Conclusion This registry provides a straightforward, no-cost mechanism for data sharing and contacting patients for clinical trials or research participation, which is important given the recruitment challenges for clinical trials for rare diseases. This is the first publication to present results from a global patient registry for Leigh Syndrome, with details on a variety of patient-specific and caregiver outcomes reported for the first time. Additionally, this registry is the first for any mitochondrial disease with nearly 70% of participants residing outside of the United States. Future efforts include continued publication of results and further collaboration with patients, industry partners, and researchers.
