Leigh Syndrome

Overview

Leigh syndrome is a severe, progressive disorder of mitochondrial energy production—the process cells use to make usable energy. It usually begins in infancy or early childhood and can cause developmental delay or loss of skills, low muscle tone, movement problems, seizures, feeding difficulties, breathing abnormalities, and characteristic injury to deep brain structures. It is genetically diverse: pathogenic changes in mitochondrial DNA or in more than 120 nuclear genes can produce the Leigh syndrome spectrum. GeneReviews overview

Prognosis varies substantially by genetic cause and age at onset, but is often poor: episodic deteriorations and progressive neurological decline are common, and up to half of people with nuclear gene-encoded Leigh syndrome spectrum die by age three. Current care is principally multidisciplinary and supportive—management of seizures, dystonia, nutrition, breathing, heart disease, and metabolic crises—while a minority of genetically defined forms have targeted treatments, such as biotin and thiamine for SLC19A3-related disease, coenzyme Q10 for primary coenzyme Q10 deficiency, or a ketogenic diet for some pyruvate dehydrogenase deficiencies. GeneReviews overview

Scope of Recent Research (2020–present)

Research activity has increased, but the field remains early in its path toward a cure because “Leigh syndrome” represents many biologically distinct diseases rather than one defect. The dominant questions are how to replace a defective nuclear gene safely in the brain and body, how to correct or compensate for mitochondrial dysfunction caused by mitochondrial-DNA variants, and whether gene-agnostic approaches—improving cellular metabolism, reducing inflammation, or modifying stress responses—can slow progression across multiple causes. The strongest curative evidence is still in animal models, while human studies mainly test disease-modifying or symptom-stabilizing drugs. NDUFS4 gene replacement in mice Leigh syndrome natural-history study

Major Breakthroughs and Emerging Therapies

The most direct potential cure is gene replacement for forms caused by nuclear-DNA defects. In 2020, researchers used an adeno-associated virus (AAV), a modified delivery virus, to restore Ndufs4 expression in adult mice lacking this complex-I gene. Treated mice showed delayed neurological decline and markedly extended survival; half survived to 250 days, far beyond untreated animals. NDUFS4 gene replacement in mice A later study found that two systemic doses of self-complementary AAV9 carrying human NDUFS4 prevented the severe Leigh-like disease phenotype in Ndufs4-knockout mice. Dual-dose AAV9-NDUFS4 study These studies are important proof of principle, but they are not yet human trials and apply directly only to the relatively rare NDUFS4-related form.

A separate emerging strategy aims to modify the damaging downstream biology rather than correct the causative mutation. Work in the Ndufs4-knockout mouse identified neuroinflammation as a driver of disease: reducing disease-associated leukocytes, or inhibiting the immune-cell signaling enzyme PI3K-gamma, prevented or substantially reduced brain lesions, seizures, respiratory dysfunction, metabolic abnormalities, and early death in that model. Leukocyte-targeting study This has shifted the field’s view of Leigh syndrome from a purely energy-deficiency disorder toward one in which immune responses may also amplify brain injury.

The most advanced recent drug evidence comes from Japan for SPP-004, a combination of 5-aminolevulinic acid hydrochloride and sodium ferrous citrate intended to support mitochondrial heme-related metabolism. In a randomized-withdrawal Phase III study, 54 people first received open-label treatment; 28 initial responders then entered a 48-week blinded comparison. In the evaluable randomized group, discontinuation for inadequate efficacy was lower with SPP-004 than placebo—15.4% versus 50.0%—and reported adverse drug reactions were mild. SPP-004 Phase III trial This is promising evidence of maintained clinical benefit in selected initial responders, but it does not establish reversal of the underlying genetic disease or a cure.

Precision treatment remains important even before gene therapy arrives. For certain Leigh-spectrum disorders, early genetic diagnosis can identify therapies that may substantially alter the course of disease, including vitamin-responsive conditions and primary coenzyme Q10 deficiency. GeneReviews overview For mitochondrial-DNA disease, programmable mitochondrial nucleases and base-editing platforms are being developed to reduce the proportion of mutated mitochondrial genomes in cells, but these approaches remain experimental and have not yet become clinical treatments for Leigh syndrome. Mitochondrial DNA-associated Leigh syndrome overview

Clinical Trials and Experimental Approaches

SPP-004 is the clearest recent interventional success specifically in Leigh syndrome. Its earlier exploratory study enrolled ten children younger than two years, used a 12-week randomized placebo-controlled period followed by open-label treatment, and continued treatment for up to 204 weeks; the study was too small to demonstrate a statistically significant between-group difference in the blinded period, but provided the rationale for the later confirmatory trial. SPP-004 exploratory and extension study

Several ongoing or planned studies are testing broader disease-modifying treatments rather than genetic correction. Thiogenesis Therapeutics is sponsoring a partially randomized, placebo-controlled Phase 2a dose-ranging study of TTI-0102 in adults and children with Leigh syndrome spectrum, designed to inform a subsequent Phase 2b/3 program. TTI-0102 Phase 2a trial At Children’s Hospital of Philadelphia, a pilot Phase 2 study with long-term extension is evaluating daily oral sirolimus in genetically confirmed Leigh syndrome, using safety, movement-disorder, and mitochondrial disease severity measures. Sirolimus Phase 2 trial

The clinical record also illustrates the difficulty of translating encouraging mouse findings. Aadi Bioscience’s planned Phase 2a trial of intravenous nab-sirolimus (ABI-009) was withdrawn before enrollment after its investigational-new-drug application was withdrawn; actual enrollment was zero. ABI-009 Phase 2a record Vatiquinone, an antioxidant-oriented investigational medicine formerly called EPI-743, completed a Phase 2/3 trial in 68 people with refractory epilepsy and mitochondrial disease, including Leigh syndrome, but the registry does not report study results. Vatiquinone refractory-epilepsy trial

Methodologies and Scientific Approaches

Researchers combine genetically precise animal models with human patient-derived systems. The Ndufs4-knockout mouse is widely used to test gene replacement, metabolic interventions, and anti-inflammatory approaches because it develops brain lesions and progressive neurological disease resembling a defined form of Leigh syndrome. NDUFS4 mouse-model review Human induced pluripotent stem cells—patient cells reprogrammed into versatile stem cells—are being converted into neurons and three-dimensional brain organoids to study early disease processes and test candidate drugs in a patient-relevant setting. Leigh syndrome cerebral-organoid model

Clinical-trial readiness depends on better natural-history data and measurable outcomes. Researchers are using repeated neurological assessments, MRI, lactate, and blood markers such as fibroblast growth factor 21 and growth differentiation factor 15, alongside the Newcastle Pediatric Mitochondrial Disease Scale, to track progression and treatment response. SPP-004 Phase III trial The International Registry for Leigh Syndrome and related natural-history initiatives are designed to assemble the longitudinal clinical and laboratory data needed to identify prognostic factors and create feasible trials in a rare, genetically heterogeneous population. International Leigh syndrome registry

Leading Institutions and Funding

Important academic and clinical contributors include the University of Padova group led by Massimo Zeviani, which has advanced NDUFS4 AAV gene-replacement studies; Seattle Children’s Research Institute, which has developed the inflammation-focused work in the Ndufs4 model; and Children’s Hospital of Philadelphia, which is conducting the sirolimus trial. Dual-dose AAV9-NDUFS4 study Leukocyte-targeting study Sirolimus Phase 2 trial

Patient-led and public funding are also important. In 2021, the Leigh Syndrome International Consortium awarded US$150,000 across five teams, including US$50,000 to the University of Padova for gene therapy in mouse models of Leigh syndrome. LSIC 2021 grant cycle The NIH-supported North American Mitochondrial Disease Consortium provides infrastructure for mitochondrial-disease studies and training through grant U54NS078059, while an NIH award to Washington University began in 2024 with US$596,783 for research on mitochondrial-transfer pathways in Leigh-like disease. NAMDC funding program NIH mitochondrial-transfer award

Strengths, Limitations, and Challenges

A major strength is that researchers now have credible biological targets rather than only general supportive care: AAV-mediated replacement can rescue a single-gene disease model, and inflammatory-cell targeting can prevent extensive pathology in another preclinical setting. NDUFS4 gene replacement in mice Leukocyte-targeting study Human studies of SPP-004 and sirolimus also show that rigorously designed trials are becoming more feasible, supported by better rating scales, registries, and natural-history data. SPP-004 Phase III trial Sirolimus Phase 2 trial

The central limitation is heterogeneity: a therapy that corrects NDUFS4 cannot correct the many other nuclear or mitochondrial-DNA causes of Leigh syndrome. GeneReviews overview Gene therapy must also reach enough brain and peripheral tissues, avoid immune toxicity, provide durable expression, and be given early enough to prevent irreversible injury. Drug trials face small populations, variable progression, developmental differences, and endpoints that may not capture meaningful changes equally across children and adults. Leigh syndrome natural-history study

Outlook and Future Directions

Leigh syndrome is not close to a broadly applicable cure as of August 8, 2026, but the path is becoming clearer. The milestones to watch are: human safety studies of gene replacement for a defined nuclear-gene subtype; reproducible confirmation of SPP-004’s benefit and its regulatory path; results from the sirolimus and TTI-0102 programs; and whether patient-derived cellular models can identify genotype-specific therapies fast enough for children before severe neurological injury occurs. The most realistic near-term goal is earlier diagnosis plus disease stabilization or prevention of progression in selected forms; durable cures will likely require separate precision strategies for nuclear-DNA and mitochondrial-DNA causes. TTI-0102 Phase 2a trial Mitochondrial DNA-associated Leigh syndrome overview

References

• ABI-009 Phase 2a record — ClinicalTrials.gov, 2026.
• Dual-dose AAV9-NDUFS4 study — Di Meo et al., 2022.
• GeneReviews overview — Rahman, Thorburn, and Ball; GeneReviews, updated 2025.
• International Leigh syndrome registry — University of Texas Health Science Center at Houston, 2023.
• Leigh syndrome cerebral-organoid model — Romero-Morales et al., 2022.
• Leigh syndrome natural-history study — Stenton et al., 2022.
• Leukocyte-targeting study — Stokes et al., 2022.
• LSIC 2021 grant cycle — Leigh Syndrome International Consortium, 2021.
• Mitochondrial DNA-associated Leigh syndrome overview — GeneReviews, updated 2025.
• NAMDC funding program — North American Mitochondrial Disease Consortium, 2026.
• NDUFS4 gene replacement in mice — Silva-Pinheiro et al., 2020.
• NDUFS4 mouse-model review — Bird et al., 2022.
• NIH mitochondrial-transfer award — U.S. Department of Health and Human Services, 2024.
• Sirolimus Phase 2 trial — Children’s Hospital of Philadelphia, 2026.
• SPP-004 exploratory and extension study — Abe et al., 2025.
• SPP-004 Phase III trial — Abe et al., 2025.
• TTI-0102 Phase 2a trial — Thiogenesis Therapeutics, 2026.
• Vatiquinone refractory-epilepsy trial — PTC Therapeutics, 2023.