RARE DISEASE
Mitochondrial DNA-associated Leigh syndrome
Mitochondrial DNA-associated Leigh syndrome
Mitochondrial DNA-associated Leigh syndrome
Synonyms: MILS, Maternally-inherited Leigh disease, Maternally-inherited infantile subacute necrotizing encephalopathy, mtDNA-associated Leigh syndrome
Synonyms: MILS, Maternally-inherited Leigh disease, Maternally-inherited infantile subacute necrotizing encephalopathy, mtDNA-associated Leigh syndrome
Synonyms: MILS, Maternally-inherited Leigh disease, Maternally-inherited infantile subacute necrotizing encephalopathy, mtDNA-associated Leigh syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Mitochondrial DNA-associated Leigh syndrome spectrum (mtDNA-LSS) is a maternally inherited neurodegenerative disorder caused by mtDNA mutations impairing oxidative phosphorylation. Typically presenting at 3-12 months after metabolic stressors, it features developmental regression, hypotonia, seizures, brainstem dysfunction (respiratory failure, dysphagia), and extraneurologic manifestations like cardiomyopathy. Diagnosis relies on clinical criteria, neuroimaging showing basal ganglia/brainstem lesions, and mtDNA variant identification. Prognosis is poor, with 50% mortality by age 3 and progressive multisystem decline [1][6][11].
Burden
Median survival: 3 years for early-onset; up to early 20s for later-onset forms [2][4]
42% develop severe functional impairment (mobility, feeding, communication) within 3 years [4][16]
High healthcare utilization: 85% require multidisciplinary care, 62% need gastrostomy, 33% develop cardiomyopathy [4][16]
Therapies
Supportive care: Sodium bicarbonate for acidosis, antiseizure medications, baclofen/dystonia management, respiratory support [1][8]
Metabolic support: Vitamin cocktails (CoQ10, thiamine), ketogenic diet for PDH deficiency [2][8]
Emerging therapies: EPI-743 (redox modulator), L-arginine for stroke-like episodes, gene-specific trials (e.g., MT-ATP6) [3][8][13]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
38 drug discovery papers about Mitochondrial DNA-associated Leigh syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
38 drug discovery papers about Mitochondrial DNA-associated Leigh syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-01-26 | Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
2025-04-01 | Exploring of Recent pharmaceutical applications of Sildenafil in medicine: review article
Sildenafil (SIL), a phosphodiesterase enzyme 5 (PDE5) inhibitor, has become a prominent molecule for the erectile dysfunction (ED) treatment. It has assumed a major role in the treatment of this disease due to the demonstrated efficacy, ease of use, good tolerability, and positive impact on the quality of life of patients. SIL has multiple pharmacological actions that grasp the researchers’ attention due to its various pharmaceutical applications. In addition to its efficacy in treating erectile dysfunction (ED), SIL is extensively employed in the treatment of intrauterine growth retardation (IUGR), benign prostatic hypertrophy (BPH), Eisenmenger's syndrome and Mountain sickness, kidney diseases, pulmonary arterial hypertension. Furthermore, SIL also exhibits promise antiproliferative, anti-Alzheimer, and anti-inflammatory properties. Finally, the pharmacodynamics, pharmacokinetics, drug interactions, and SIL toxicity were investigated. The adequate pharmacokinetic properties of SIL and the diverse therapeutic applications have encouraged researchers to generate new applications that have either been approved by the FDA or are currently undergoing clinical trials like osteoarthritis (OA), COVID-19, female urinary incontinence (UI) and Maternally Inherited Leigh syndrome (MILS).
2025-01-23 | Precise modelling of mitochondrial diseases using optimized mitoBEs.
The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
2026-01-26 | Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
2025-04-01 | Exploring of Recent pharmaceutical applications of Sildenafil in medicine: review article
Sildenafil (SIL), a phosphodiesterase enzyme 5 (PDE5) inhibitor, has become a prominent molecule for the erectile dysfunction (ED) treatment. It has assumed a major role in the treatment of this disease due to the demonstrated efficacy, ease of use, good tolerability, and positive impact on the quality of life of patients. SIL has multiple pharmacological actions that grasp the researchers’ attention due to its various pharmaceutical applications. In addition to its efficacy in treating erectile dysfunction (ED), SIL is extensively employed in the treatment of intrauterine growth retardation (IUGR), benign prostatic hypertrophy (BPH), Eisenmenger's syndrome and Mountain sickness, kidney diseases, pulmonary arterial hypertension. Furthermore, SIL also exhibits promise antiproliferative, anti-Alzheimer, and anti-inflammatory properties. Finally, the pharmacodynamics, pharmacokinetics, drug interactions, and SIL toxicity were investigated. The adequate pharmacokinetic properties of SIL and the diverse therapeutic applications have encouraged researchers to generate new applications that have either been approved by the FDA or are currently undergoing clinical trials like osteoarthritis (OA), COVID-19, female urinary incontinence (UI) and Maternally Inherited Leigh syndrome (MILS).
2025-01-23 | Precise modelling of mitochondrial diseases using optimized mitoBEs.
The development of animal models is crucial for studying and treating mitochondrial diseases. Here we optimized adenine and cytosine deaminases to reduce off-target effects on the transcriptome and the mitochondrial genome, improving the accuracy and efficiency of our newly developed mitochondrial base editors (mitoBEs)1. Using these upgraded mitoBEs (version 2 (v2)), we targeted 70 mouse mitochondrial DNA mutations analogous to human pathogenic variants2, establishing a foundation for mitochondrial disease mouse models. Circular RNA-encoded mitoBEs v2 achieved up to 82% editing efficiency in mice without detectable off-target effects in the nuclear genome. The edited mitochondrial DNA persisted across various tissues and was maternally inherited, resulting in F1 generation mice with mutation loads as high as 100% and some mice exhibiting editing only at the target site. By optimizing the transcription activator-like effector (TALE) binding site, we developed a single-base-editing mouse model for the mt-Nd5 A12784G mutation. Phenotypic evaluations led to the creation of mouse models for the mt-Atp6 T8591C and mt-Nd5 A12784G mutations, exhibiting phenotypes corresponding to the reduced heart rate seen in Leigh syndrome and the vision loss characteristic of Leber's hereditary optic neuropathy, respectively. Moreover, the mt-Atp6 T8591C mutation proved to be more deleterious than mt-Nd5 A12784G, affecting embryonic development and rapidly diminishing through successive generations. These upgraded mitoBEs offer a highly efficient and precise strategy for constructing mitochondrial disease models, laying a foundation for further research in this field.
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