RARE DISEASE
Multiple mitochondrial DNA deletion syndrome
Multiple mitochondrial DNA deletion syndrome
Multiple mitochondrial DNA deletion syndrome
Synonyms: Multiple mtDNA deletion syndrome
Synonyms: Multiple mtDNA deletion syndrome
Synonyms: Multiple mtDNA deletion syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Multiple Mitochondrial DNA Deletion Syndromes (MMDS) are rare genetic disorders characterized by impaired mtDNA maintenance, leading to progressive accumulation of mitochondrial DNA deletions. These defects disrupt oxidative phosphorylation, causing multisystem involvement with clinical features such as progressive external ophthalmoplegia, myopathy, neuropathies, ataxia, and organ dysfunction. MMDS are primarily caused by autosomal recessive or dominant nuclear gene mutations (e.g., POLG, TWNK, DGUOK) affecting mtDNA replication/repair, though sporadic mtDNA deletions also occur [1][3][16].
Burden
High morbidity: 65% develop skeletal muscle weakness, 40% CNS involvement (ataxia, cognitive decline), and 25% exercise intolerance [1][12].
Mortality: Median survival 11.5 years post-onset in pediatric cohorts; fatal hepatic/neurological complications common in early-onset forms [6][12].
Diagnostic challenges: Mean 6.3-year delay from symptom onset to genetic confirmation [14].
Therapies
Supportive care: Multidisciplinary management (e.g., cardiac pacing, PT/OT, nutritional support) [14].
Experimental approaches: Nucleoside bypass therapy (TK2-related cases), liver transplantation for hepatic forms, and gene therapy trials (AAV-mediated DGUOK delivery in preclinical models) [3][8][13].
Symptomatic agents: Coenzyme Q10, antioxidants, and vitamins (limited evidence) [13][14].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
8 drug discovery papers about Multiple mitochondrial DNA deletion syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
8 drug discovery papers about Multiple mitochondrial DNA deletion syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-07-22 | Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPR mt ) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.
2024-08-28 | Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults.
Doxecitine (deoxycytidine [dC]) and doxribtimine (deoxythymidine [dT]) powder for oral solution is a 1:1 mixture consisting of equal weights 2'-deoxycytidine (dC) and 2'-deoxythymidine (dT). Doxecitine and doxribtimine (referred to as study drug) is being developed as treatment for people with thymidine kinase 2 deficiency (TK2d). TK2d is an ultra-rare mitochondrial DNA depletion and multiple deletion syndrome characterized by progressive muscle weakness and premature death. Here, we report the pharmacokinetics (PK), the effect of food, and the tolerability of 2 study drug formulations, evaluated in 2 studies (Study MT-1621-103 and Study MT-1621-105). A sequential, ascending 1:1 dose ratio was used for both studies (n = 14 healthy volunteer adult participants/study). After a 28-day (Study MT-1621-103) or 35-day (Study MT-1621-105) screening period, participants fasted overnight and sequentially received 86.6, 173.4, and 266.6 mg/kg study drug with a 48-hour PK assessment period and 48-hour washout period between doses. After 48 additional hours, participants were fed a high-fat meal and received 266.6 mg/kg study drug. Plasma and urine were collected before dosing and throughout the 48-hour PK period. dC and dT concentrations were analyzed by validated liquid chromatography mass spectrometry methods. Safety was evaluated throughout the study and at 2-week follow-up. Plasma levels of dC and dT increased rapidly and dose-dependently above endogenous levels for both formulations, with a median Tmax of 1 to 2 hours under fasting conditions. Post-dose plasma dC and dT concentrations declined to nearly pre-dose (baseline) concentrations after 8 to 12 hours, suggesting rapid elimination. Peak and extent of plasma exposure (baseline-corrected Cmax and AUC0-t) tended to increase less than dose-proportionally for plasma dC and greater than dose-proportionally for plasma dT. PK variability of dC and dT was moderate-to-high (>30%). Administration with food delayed Tmax to a median of 2 to 4 hours and increased plasma exposure: baseline-corrected plasma dC Cmax and AUC0-t increased by ∼79% to 96% and 137% to 250%, respectively, and dT Cmax and AUC0-t increased by 27% to 29% and 74% to 89%, respectively, indicating a significant food effect. Renal clearance played a minor role in the elimination of systemically available intact dC and dT (Fe<0.3%). The study drug was generally well tolerated; most frequent study-drug-related adverse events (AEs) were diarrhea (n = 4/29, 14%) and dizziness (n = 3/29, 10%). Most AEs were mild-to-moderate in severity. Doxecitine and doxribtimine are orally bioavailable in the intended clinical dose range. The PK profile supports a formulation consisting of equal doses of doxecitine and doxribtimine, a 3-times-daily dosing regimen, and administration with food.
2022-07-04 | RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS.
2022-02-22 | Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability.
Mitochondrial DNA (mtDNA) maintenance is critical for oxidative phosphorylation (OXPHOS) since some subunits of the respiratory chain complexes are mitochondrially encoded. Pathological mutations in nuclear genes involved in the mtDNA metabolism may result in a quantitative decrease in mtDNA levels, referred to as mtDNA depletion, or in qualitative defects in mtDNA, especially in multiple deletions. Since, in the last decade, most of the novel mutations have been identified through whole-exome sequencing, it is crucial to confirm the pathogenicity by functional analysis in the appropriate model systems. Among these, the yeast Saccharomyces cerevisiae has proved to be a good model for studying mutations associated with mtDNA instability. This review focuses on the use of yeast for evaluating the pathogenicity of mutations in six genes, MPV17/SYM1, MRM2/MRM2, OPA1/MGM1, POLG/MIP1, RRM2B/RNR2, and SLC25A4/AAC2, all associated with mtDNA depletion or multiple deletions. We highlight the techniques used to construct a specific model and to measure the mtDNA instability as well as the main results obtained. We then report the contribution that yeast has given in understanding the pathogenic mechanisms of the mutant variants, in finding the genetic suppressors of the mitochondrial defects and in the discovery of molecules able to improve the mtDNA stability.
2019-02-05 | 8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease.
Intravenous (IV) arginine has been reported to ameliorate acute metabolic stroke symptoms in adult patients with Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) syndrome, where its therapeutic benefit is postulated to result from arginine acting as a nitric oxide donor to reverse vasospasm. Further, reduced plasma arginine may occur in mitochondrial disease since the biosynthesis of arginine's precursor, citrulline, requires ATP. Metabolic strokes occur across a wide array of primary mitochondrial diseases having diverse molecular etiologies that are likely to share similar pathophysiologic mechanisms. Therefore, IV arginine has been increasingly used for the acute clinical treatment of metabolic stroke across a broad mitochondrial disease population. We performed retrospective analysis of a large cohort of subjects who were under 18 years of age at IRB #08-6177 study enrollment and had molecularly-confirmed primary mitochondrial disease (n = 71, excluding the common MELAS m.3243A>G mutation). 9 unrelated subjects in this cohort received acute arginine IV treatment for one or more stroke-like episodes (n = 17 total episodes) between 2009 and 2016 at the Children's Hospital of Philadelphia. Retrospectively reviewed data included subject genotype, clinical symptoms, age, arginine dosing, neuroimaging (if performed), prophylactic therapies, and adverse events. Genetic etiologies of subjects who presented with acute metabolic strokes included 4 mitochondrial DNA (mtDNA) pathogenic point mutations, 1 mtDNA deletion, and 4 nuclear gene disorders. Subject age ranged from 19 months to 23 years at the time of any metabolic stroke episode (median, 8 years). 3 subjects had recurrent stroke episodes. 70% of subjects were on prophylactic arginine or citrulline therapy at the time of a stroke-like episode. IV arginine was initiated on initial presentation in 65% of cases. IV arginine was given for 1-7 days (median, 1 day). A positive clinical response to IV arginine occurred in 47% of stroke-like episodes; an additional 6% of episodes showed clinical benefit from multiple simultaneous treatments that included arginine, confounding sole interpretation of arginine effect. All IV arginine-responsive stroke-like episodes (n = 8) received treatment immediately on presentation (p = .003). Interestingly, the presence of unilateral symptoms strongly predicted arginine response (p = .02, Chi-Square); however, almost all of these cases immediately received IV arginine, confounding interpretation of causality direction. Suggestive trends toward increased IV arginine response were seen in subjects with mtDNA relative to nDNA mutations and in older pediatric subjects, although statistical significance was not reached possibly due to small sample size. No adverse events, including hypotensive episodes, from IV arginine therapy were reported. Single-center retrospective analysis suggests that IV arginine therapy yields significant therapeutic benefit with little risk in pediatric mitochondrial disease stroke subjects across a wide range of genetic etiologies beyond classical MELAS. Acute hemiplegic stroke, in particular, was highly responsive to IV arginine treatment. Prospective studies with consistent arginine dosing, and pre- and post-neuroimaging, will further inform the clinical utility of IV arginine therapy for acute metabolic stroke in pediatric mitochondrial disease.
small molecules
2025-07-22 | Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model.
S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPR mt ) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.
2024-08-28 | Pharmacokinetics and Safety of a 1:1 Mixture of Doxecitine and Doxribtimine: Open-label Phase 1 Single Ascending Dose and Food Effect Studies in Healthy Adults.
Doxecitine (deoxycytidine [dC]) and doxribtimine (deoxythymidine [dT]) powder for oral solution is a 1:1 mixture consisting of equal weights 2'-deoxycytidine (dC) and 2'-deoxythymidine (dT). Doxecitine and doxribtimine (referred to as study drug) is being developed as treatment for people with thymidine kinase 2 deficiency (TK2d). TK2d is an ultra-rare mitochondrial DNA depletion and multiple deletion syndrome characterized by progressive muscle weakness and premature death. Here, we report the pharmacokinetics (PK), the effect of food, and the tolerability of 2 study drug formulations, evaluated in 2 studies (Study MT-1621-103 and Study MT-1621-105). A sequential, ascending 1:1 dose ratio was used for both studies (n = 14 healthy volunteer adult participants/study). After a 28-day (Study MT-1621-103) or 35-day (Study MT-1621-105) screening period, participants fasted overnight and sequentially received 86.6, 173.4, and 266.6 mg/kg study drug with a 48-hour PK assessment period and 48-hour washout period between doses. After 48 additional hours, participants were fed a high-fat meal and received 266.6 mg/kg study drug. Plasma and urine were collected before dosing and throughout the 48-hour PK period. dC and dT concentrations were analyzed by validated liquid chromatography mass spectrometry methods. Safety was evaluated throughout the study and at 2-week follow-up. Plasma levels of dC and dT increased rapidly and dose-dependently above endogenous levels for both formulations, with a median Tmax of 1 to 2 hours under fasting conditions. Post-dose plasma dC and dT concentrations declined to nearly pre-dose (baseline) concentrations after 8 to 12 hours, suggesting rapid elimination. Peak and extent of plasma exposure (baseline-corrected Cmax and AUC0-t) tended to increase less than dose-proportionally for plasma dC and greater than dose-proportionally for plasma dT. PK variability of dC and dT was moderate-to-high (>30%). Administration with food delayed Tmax to a median of 2 to 4 hours and increased plasma exposure: baseline-corrected plasma dC Cmax and AUC0-t increased by ∼79% to 96% and 137% to 250%, respectively, and dT Cmax and AUC0-t increased by 27% to 29% and 74% to 89%, respectively, indicating a significant food effect. Renal clearance played a minor role in the elimination of systemically available intact dC and dT (Fe<0.3%). The study drug was generally well tolerated; most frequent study-drug-related adverse events (AEs) were diarrhea (n = 4/29, 14%) and dizziness (n = 3/29, 10%). Most AEs were mild-to-moderate in severity. Doxecitine and doxribtimine are orally bioavailable in the intended clinical dose range. The PK profile supports a formulation consisting of equal doses of doxecitine and doxribtimine, a 3-times-daily dosing regimen, and administration with food.
2022-07-04 | RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.
Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS.
2022-02-22 | Saccharomyces cerevisiae as a Tool for Studying Mutations in Nuclear Genes Involved in Diseases Caused by Mitochondrial DNA Instability.
Mitochondrial DNA (mtDNA) maintenance is critical for oxidative phosphorylation (OXPHOS) since some subunits of the respiratory chain complexes are mitochondrially encoded. Pathological mutations in nuclear genes involved in the mtDNA metabolism may result in a quantitative decrease in mtDNA levels, referred to as mtDNA depletion, or in qualitative defects in mtDNA, especially in multiple deletions. Since, in the last decade, most of the novel mutations have been identified through whole-exome sequencing, it is crucial to confirm the pathogenicity by functional analysis in the appropriate model systems. Among these, the yeast Saccharomyces cerevisiae has proved to be a good model for studying mutations associated with mtDNA instability. This review focuses on the use of yeast for evaluating the pathogenicity of mutations in six genes, MPV17/SYM1, MRM2/MRM2, OPA1/MGM1, POLG/MIP1, RRM2B/RNR2, and SLC25A4/AAC2, all associated with mtDNA depletion or multiple deletions. We highlight the techniques used to construct a specific model and to measure the mtDNA instability as well as the main results obtained. We then report the contribution that yeast has given in understanding the pathogenic mechanisms of the mutant variants, in finding the genetic suppressors of the mitochondrial defects and in the discovery of molecules able to improve the mtDNA stability.
2019-02-05 | 8-year retrospective analysis of intravenous arginine therapy for acute metabolic strokes in pediatric mitochondrial disease.
Intravenous (IV) arginine has been reported to ameliorate acute metabolic stroke symptoms in adult patients with Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) syndrome, where its therapeutic benefit is postulated to result from arginine acting as a nitric oxide donor to reverse vasospasm. Further, reduced plasma arginine may occur in mitochondrial disease since the biosynthesis of arginine's precursor, citrulline, requires ATP. Metabolic strokes occur across a wide array of primary mitochondrial diseases having diverse molecular etiologies that are likely to share similar pathophysiologic mechanisms. Therefore, IV arginine has been increasingly used for the acute clinical treatment of metabolic stroke across a broad mitochondrial disease population. We performed retrospective analysis of a large cohort of subjects who were under 18 years of age at IRB #08-6177 study enrollment and had molecularly-confirmed primary mitochondrial disease (n = 71, excluding the common MELAS m.3243A>G mutation). 9 unrelated subjects in this cohort received acute arginine IV treatment for one or more stroke-like episodes (n = 17 total episodes) between 2009 and 2016 at the Children's Hospital of Philadelphia. Retrospectively reviewed data included subject genotype, clinical symptoms, age, arginine dosing, neuroimaging (if performed), prophylactic therapies, and adverse events. Genetic etiologies of subjects who presented with acute metabolic strokes included 4 mitochondrial DNA (mtDNA) pathogenic point mutations, 1 mtDNA deletion, and 4 nuclear gene disorders. Subject age ranged from 19 months to 23 years at the time of any metabolic stroke episode (median, 8 years). 3 subjects had recurrent stroke episodes. 70% of subjects were on prophylactic arginine or citrulline therapy at the time of a stroke-like episode. IV arginine was initiated on initial presentation in 65% of cases. IV arginine was given for 1-7 days (median, 1 day). A positive clinical response to IV arginine occurred in 47% of stroke-like episodes; an additional 6% of episodes showed clinical benefit from multiple simultaneous treatments that included arginine, confounding sole interpretation of arginine effect. All IV arginine-responsive stroke-like episodes (n = 8) received treatment immediately on presentation (p = .003). Interestingly, the presence of unilateral symptoms strongly predicted arginine response (p = .02, Chi-Square); however, almost all of these cases immediately received IV arginine, confounding interpretation of causality direction. Suggestive trends toward increased IV arginine response were seen in subjects with mtDNA relative to nDNA mutations and in older pediatric subjects, although statistical significance was not reached possibly due to small sample size. No adverse events, including hypotensive episodes, from IV arginine therapy were reported. Single-center retrospective analysis suggests that IV arginine therapy yields significant therapeutic benefit with little risk in pediatric mitochondrial disease stroke subjects across a wide range of genetic etiologies beyond classical MELAS. Acute hemiplegic stroke, in particular, was highly responsive to IV arginine treatment. Prospective studies with consistent arginine dosing, and pre- and post-neuroimaging, will further inform the clinical utility of IV arginine therapy for acute metabolic stroke in pediatric mitochondrial disease.
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