SNPMiner Trials by Shray Alag


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Report for Mutation A3243G

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 6 clinical trials

Clinical Trials


1 Investigation of Clinical Syndromes Associated With mtDNA Point Mutations: MELAS/DCA Clinical Trial

Patients with the MELAS syndrome experience devastating mental impairment. This study will evaluate the effectiveness of the drug dichloroacetate (DCA) to reduce the symptoms of MELAS.

NCT00068913 MELAS Syndrome Drug: Dichloroacetate
MeSH:MELAS Syndrome Syndrome

Inclusion Criteria - A3243G mtDNA point mutation or maternally related to someone who has the mutation - Symptomatic with MELAS, including previous seizure or stroke - Certain laboratory values - Ability to comply with the study protocol Inclusion Criteria - A3243G mtDNA point mutation or maternally related to someone who has the mutation - Symptomatic with MELAS, including previous seizure or stroke - Certain laboratory values - Ability to comply with the study protocol MELAS Syndrome MELAS Syndrome Syndrome Although many organ systems are affected by mitochondrial (mt) DNA point mutations, the nervous system is particularly vulnerable. --- A3243G ---

Inclusion Criteria - A3243G mtDNA point mutation or maternally related to someone who has the mutation - Symptomatic with MELAS, including previous seizure or stroke - Certain laboratory values - Ability to comply with the study protocol Inclusion Criteria - A3243G mtDNA point mutation or maternally related to someone who has the mutation - Symptomatic with MELAS, including previous seizure or stroke - Certain laboratory values - Ability to comply with the study protocol MELAS Syndrome MELAS Syndrome Syndrome Although many organ systems are affected by mitochondrial (mt) DNA point mutations, the nervous system is particularly vulnerable. --- A3243G --- --- A3243G ---

Patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome have the A3243G point mutation and elevated brain lactate levels. --- A3243G ---

Patients with the A3243G mitochondrial mutation and who have had either a stroke or a seizure will be enrolled in this study. --- A3243G ---


2 A Phase IIa Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Study of Idebenone in the Treatment of Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like Episodes

The purpose of this study is to compare the efficacy of two (2) different doses of idebenone with that of a placebo over a one month period on cerebral lactate concentration as measured by magnetic resonance spectroscopy.

NCT00887562 MELAS Syndrome Drug: Idebenone Drug: Idebenone Other: Placebo
MeSH:MELAS Syndrome Brain Diseases Acidosis Acidosis, Lactic
HPO:Acidosis Encephalopathy Lactic acidosis Metabolic acidosis

Inclusion Criteria: - Diagnosis of MELAS with confirmed A3243G mtDNA mutation, or evidence of central nervous system involvement (cognitive problems, migraines, memory loss) - Cerebral lactate level equal to or greater than 5.0 i.u. at baseline - Patients at least 8 and < 65 years of age at baseline - Patients with a body weight > 37 kg/82 lbs at baseline - Stable co-medication/vitamins/supplements within 1 month prior to baseline - Patients who in the opinion of the investigator are able to comply with the requirements of the study, including swallowing the study medication - Negative urine pregnancy test at screening and baseline (female patients of childbearing potential) Exclusion Criteria: - Contraindication to MRS (e.g. --- A3243G ---

metal implant, claustrophobia) - Stroke like event within 2 months prior to baseline - Treatment with idebenone at any dose, or coenzyme Q10 at doses above 100mg/d within 1 month prior to baseline - Inadequate contraception use - Pregnancy and/or breast-feeding - Clinically significant abnormalities of clinical hematology or biochemistry including, but not limited to, elevations greater than 1.5 times the upper limit of normal of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or creatinine - Current abuse of drugs or alcohol - Participation in a trial of another investigational drug within the last month - Other factor that, in the investigator's opinion, excludes the patient from entering the study Inclusion Criteria: - Diagnosis of MELAS with confirmed A3243G mtDNA mutation, or evidence of central nervous system involvement (cognitive problems, migraines, memory loss) - Cerebral lactate level equal to or greater than 5.0 i.u. at baseline - Patients at least 8 and < 65 years of age at baseline - Patients with a body weight > 37 kg/82 lbs at baseline - Stable co-medication/vitamins/supplements within 1 month prior to baseline - Patients who in the opinion of the investigator are able to comply with the requirements of the study, including swallowing the study medication - Negative urine pregnancy test at screening and baseline (female patients of childbearing potential) Exclusion Criteria: - Contraindication to MRS (e.g. --- A3243G ---

Given that there is no effective treatment for MELAS, the investigators propose a Phase II proof of concept trial of idebenone to study its preliminary efficacy in patients with MELAS and the A3243G mtDNA mutation, and to study its safety and tolerability in this patient group. --- A3243G ---

The investigators propose to evaluate 21 patients with the A3243G mitochondrial DNA mutation and MELAS (defined by a history of either seizures or stroke). --- A3243G ---

Primary Outcomes

Description: To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on cerebral lactate concentration as measured by magnetic resonance spectroscopy (MRS)

Measure: Mean Change in Cerebral Lactate Concentration (as Measured by Magnetic Resonance Spectroscopy)

Time: Up to 4 weeks from baseline

Secondary Outcomes

Description: To compare the efficacy of 1 month treatment with 2 different doses of idebenone with that of placebo on venous lactate concentration

Measure: Mean Change in Venous Lactate Concentration

Time: Up to 4 weeks from baseline

Description: To assess changes following 1 month treatment with 2 different doses of idebenone with that of placebo in fatigue as assessed by the Fatigue Severity Scale (FSS). Scale score minimum is 9 (least fatigue) and maximum is 63 (maximum fatigue). Scores of 36 or less indicate possibility that patient may not be suffering from fatigue, while scores 36 and over suggest suffering from fatigue

Measure: Mean Change in Score on the Fatigue Severity Scale (FSS)

Time: Baseline and Week 4

3 A Phase 2a, Double Blind, Randomized, Placebo-controlled, 28 Day, Two-arm, Parallel Group Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation and Evidence of Impaired Mitochondrial Function

This is a phase 2a, double-blind, placebo-controlled, single-center study. Twenty-one patients who qualify for the study will be randomly assigned to either active drug or placebo. The study will take place at Newcastle University. Patients will have a 66% chance of getting active drug. Patients will be required to take study treatment orally twice a day for 28 days. A baseline visit will occur within 21 days of screening visit. All patients will be followed for 1 week after completion of study or early withdrawal from the study.

NCT01074359 Neuromuscular Disease Drug: A0001 (alpha-tocopherolquinone) Drug: Placebo
MeSH:Neuromuscular Diseases

A Phase 2a, Double Blind, Randomized, Placebo-controlled, 28 Day, Two-arm, Parallel Group Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation and Evidence of Impaired Mitochondrial Function. --- A3243G ---

Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation This is a phase 2a, double-blind, placebo-controlled, single-center study. --- A3243G ---

Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Neuromuscular Disease Neuromuscular Diseases null --- A3243G ---

Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Neuromuscular Disease Neuromuscular Diseases null --- A3243G --- --- A3243G ---

Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Neuromuscular Disease Neuromuscular Diseases null --- A3243G --- --- A3243G --- --- A3243G ---

Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Inclusion Criteria: - Diagnosis of neuromuscular symptoms due to the A3243G mitochondrial DNA point mutation - PCR/ATP ratio of <1.9 following the Cardiac MRS at screening Exclusion Criteria: - Any major illness not due to the A3243G mitochondrial DNA point mutation in the past three months or any significant ongoing chronic medical illness, especially significant central nervous neurological disease limiting capacity to carry out the study - Use of any investigational product within the past 30 days Neuromuscular Disease Neuromuscular Diseases null --- A3243G --- --- A3243G --- --- A3243G --- --- A3243G ---

Primary Outcomes

Measure: Improvement in the rate of ATP recovery ("Vmax") in cardiac muscle as measured by 31Phosphorous Magnetic Resonance Spectroscopy (31P-MRS)

Time: Baseline and Day 28

Secondary Outcomes

Measure: Improvement in cardiac structure and function as measured by Magnetic Resonance Imaging (MRI)

Time: Baseline and Day 28

Measure: Exercise tolerance as measured by a 6 minute walk test

Time: Baseline, Day 14 and Day 28

Measure: Improvement in the rate of Maximal ATP recovery (Vmax) as measured by 31Phosphorous Magnetic Resonance Spectroscopy (31P-MRS) MRI of calf muscle during a standardized isolated calf muscle procedure of 2 bouts of plantar flexion exercise

Time: Baseline and Day 28

Measure: Fasting blood lactate, fasting blood glucose, fasting blood insulin , fasting blood HbA1c levels

Time: Baseline, Day 14 and Day 28

Measure: Mitochondrial disease severity (NMDAS)

Time: Baseline and Day 28

Measure: Quality of life (SF-36® Health Survey Questionnaire)

Time: Baseline and Day 28

Measure: Global impression of clinical severity

Time: Baseline, Day 14 and Day 28

Measure: Modified fatigue impact scale

Time: Baseline, Day 14 and Day 28

4 Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.

MELAS patients suffer from exercise intolerance, weakness, poor vision or blindness, poor growth, developmental delay, and deafness. They also have unique 'stroke-like' episodes (SLEs) which are not due to blockages of large or medium arteries. These 'strokes' are thought to be due to energy failure of very small brain blood vessels combined with energy failure in the mitochondria (cell battery) of the brain cells, especially in the back region of the brain in the vision centre. This leads to visual loss and paralysis. The overall goal of this study is to better understand the mechanism of these SLEs at the level of the brain cells and small blood vessels.

NCT01603446 MELAS Syndrome Drug: L-Arginine
MeSH:MELAS Syndrome Syndrome

Inclusion Criteria: Experimental Siblings with MELAS (A3243G) syndrome - 17-23 years - Followed Neurometabolic Clinic at the Hospital for Sick Children will be studied. --- A3243G ---

Primary Outcomes

Description: We will study exercising quadriceps using our MR-compatible up-down ergometer and our well established aerobic exercise protocol at 65 % of maximal voluntary contraction.

Measure: Muscle function investigation via 31P-Magnetic resonance spectroscopy

Time: 60 to 105 minutes post dose

Secondary Outcomes

Description: Maximal incremental cycle ergometry is conducted in our CardioRespiratory Exercise Lab at HSC by our established protocols (26). Serum CK and quantitative AA (for arginine, ornithine and citrulline) will be measured pre- and post- exercise as well as eNO in order to correlate aerobic exercise parameters with serum arg and eNO levels..

Measure: Total body maximal aerobic capacity

Time: 60-75 mins post dose

Description: Functional MRI-Blood oxygen level dependent (BOLD) of brain

Measure: CerebroVascular Reactivity

Time: 75-105 mins post dose

Description: eNO will be measured using single breath on-line measurements for the assessment of lower airway Nitric Oxide

Measure: Exhaled Nitric Oxide (eNO)

Time: 75 mins pre dose, 75 mins post dose

5 A Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of ME1100 Inhalation Solution (Arbekacin Inhalation Solution) Administered to Healthy Volunteers

This is a single-center, randomized, double-blind, placebo-controlled, sequential group study. The primary objective of this study is to assess the tolerability and safety of single doses of ME1100 inhalation solution (orally inhaled arbekacin). The secondary objective is to determine the systemic exposure to, and urinary elimination of, ME1100.

NCT01907776 Healthy Drug: ME1100 inhalation solution Drug: ME1100 placebo inhalation solution

heteroplasmy) suggestive of increased risk of hearing loss (MT-RNR1 [A1555G] for mitochondrial 12S ribosomal RNA gene or MT-TS1 [A3243G] for mitochondrial transfer RNA serine 1) - History of parent, sibling or parental sibling reporting hearing loss before age 65 years - History of malignancy - History of clinically significant alcohol or drug abuse - History within last 6 months or current use of any tobacco product including e-cigarettes - Positive drug screen for drugs of abuse - Positive test for HIV, Hepatitis B or Hepatitis C - Use of any prescription or over-the-counter medications (except oral or hormonal contraceptives), herbal supplements, or vitamins within 14 days of Visit 2 - Known hypersensitivity to any aminoglycoside or bacitracin antibiotic - Female of childbearing potential with a positive urine pregnancy test, or currently breast feeding. --- A1555G --- --- A3243G ---

Primary Outcomes

Measure: Number of participants with adverse events

Time: from Baseline to Day 8-10

Measure: Number of participants with abnormal physical examinations

Time: from Baseline to Day 8-10

Measure: Number of participants with abnormal 12-lead electrocardiograms

Time: from Baseline to Day 8-10

Measure: Number of participants with abnormal vital signs

Time: from Baseline to Day 8-10

Measure: Number of participants with abnormal safety laboratory measurements

Time: from Baseline to Day 8-10

Secondary Outcomes

Measure: Serum Concentration of ME1100

Time: 5, 15, 30 minutes and 1, 2, 3, 4, 6, 8, 12, 18 and 24 hours post START of dosing

Measure: Urinary elimination of ME1100

Time: 0-6, 6-12, 12-24, 24-48 and 48-72 hours after single dosing

6 An Open-label, Single Dose Study to Assess Intrapulmonary Pharmacokinetics of ME1100 Inhalation Solution Administered to Healthy Volunteers

This is a single-center, open-label, single-dose study. The primary objective is to determine Epithelial Lining Fluid (ELF) levels of ME1100 after a single orally inhaled dose. The secondary objectives are to determine systemic exposure to inhaled ME1100 and to assess tolerability and safety of a single dose of ME1100 inhalation solution.

NCT01961830 Healthy Drug: ME1100 inhalation solution

heteroplasmy) suggestive of increased risk of hearing loss (MT-RNR1 [A1555G] for mitochondrial 12S ribosomal RNA gene or MT-TS1 [A3243G] for mitochondrial transfer RNA serine 1) - History of parent, sibling or parental sibling reporting hearing loss before age 65 years - History of malignancy - History of clinically significant alcohol or drug abuse - History within last 6 months or current use of any tobacco products including e-cigarettes. --- A1555G --- --- A3243G ---

Primary Outcomes

Description: Each subject will undergo fiber-optic bronchoscopy for the collection of bronchoalveolar lavage fluid at one of the following time points:5 minutes after END of dosing, 0.5, 1, 3, 6 and 12 hrs post START of dosing.

Measure: Pharmacokinetics profile in ELF

Time: 0-12 hours after START of Dosing

Secondary Outcomes

Measure: Serum Concentration of ME1100

Time: 2, 5, 10 minutes after END of dosing, 0.5, 1, 3, 6 and 12 hrs post START of dosing

Measure: Number of participants with abnormal safety laboratory measurements

Time: from Baseline to Day 3


HPO Nodes


HP:0001298: Encephalopathy
Genes 334
ACTL6B SLC19A3 GABRA1 TH RNASEH2C CACNA1B NDUFA6 SYNJ1 TRAK1 COG8 NDUFAF4 KYNU ND5 CLTC PNKP TCF4 TRNS2 ND2 TRAK1 SLC2A1 FGF12 KCNB1 CNTNAP2 NDUFAF1 PPP3CA MAPK10 CACNA1E TK2 PNPO SLC12A3 KCNQ5 COX3 SPTAN1 TP53 NAXE NDUFV2 BSCL2 RANBP2 TRNS1 GABRG2 NADK2 SLC1A2 MST1 GCDH TRNF DHDDS SLC6A9 KCNA2 GABRB3 SLC25A22 GRIN2B GNAO1 CHD2 ARHGEF9 FBXL4 KCNQ2 NDUFS4 SUCLG1 CAD ZNHIT3 NDUFS3 ACAD9 SLC19A3 LYRM7 SCN1B NEUROD2 PRNP TRNW CYTB CCDC88A SCN9A NDUFA6 DNM1 NDUFS1 KMT2E RANBP2 CLCNKB ACY1 DPM2 DENND5A ALG9 COX15 ITPA SLC35A1 SLC35A2 NDUFS6 GABRB2 TBCD HADH NDUFAF3 STAG1 ATP1A3 RNF13 TBCE GPT2 NDUFV1 ATP5F1D PARS2 CACNA1A SERPINI1 GLYCTK NDUFA11 ST3GAL3 NRXN1 KYNU NRXN1 TMEM126B LIAS CACNA1A ASNS ATP5F1A NDUFS3 COG8 ND1 TBCE PCCB UNC80 FCSK DNM1 ATP5F1A ARX HTRA1 SZT2 DGUOK MDH2 MDM2 TBC1D24 ND3 TBCK GABRB2 TIMMDC1 AP3B2 ADAM22 NTRK2 CPT2 GABRA5 TRIT1 NDUFAF5 KCNQ2 SLC25A22 SYNGAP1 NDUFS7 WDR45 NDUFS2 NUS1 ACSF3 SLC25A20 SCN1A SCN3A GABRB3 KCNA2 CHD2 SLC1A2 COX2 GCDH AARS1 PCK1 IBA57 COQ2 NDUFS8 COQ4 ND1 STAT2 TRNK EEF1A2 MPC1 SLC25A15 SLC13A5 KCNT2 ATP6V1A HCN1 DLD CACNA1B PIGP GRIN2D ROGDI PNPO ATAD1 CUX2 TRNV NDUFAF2 BSCL2 NDUFB10 UBA5 NAXD PHACTR1 LIPT2 GABRB1 NDUFS6 RNASEH2B ETHE1 CDKL5 NDUFAF4 TRNL1 CLCN4 GBA ACY1 AMACR PPP3CA TIMM50 HCN1 TCF4 NDUFB3 NDUFS4 ETHE1 NDUFB11 DLD SZT2 TUFM SH2D1A KCNT1 SLC22A5 GLUL GBA HMGCL TSFM BCS1L AP2M1 CNPY3 CARS2 KCNB1 FADD SYNGAP1 STXBP1 DNM1 SLC25A13 CLP1 PCCA TMEM70 HNRNPU PACS2 FRRS1L CHEK2 NECAP1 D2HGDH MEF2C EEF1A2 SLC6A1 YWHAG NBAS GPR35 COQ9 AP3B2 DHDDS PNPT1 TRNQ SLC25A12 UBA5 CNKSR2 FGF12 GUF1 SIK1 DNM1L NUBPL SUCLA2 GLS NUS1 ARHGEF9 COX1 ARV1 ARV1 NDUFA11 TBC1D24 PLCB1 DOCK7 HIBCH GABRG2 NDUFAF2 SLC25A15 WWOX CARS2 GCSH SYNJ1 NDUFV2 SCN8A ATP6V1A SLC22A5 SLC13A5 NDUFB9 HADH STXBP1 CPT1A TRAPPC12 BOLA3 XIAP FOXRED1 SIK1 SERAC1 NDUFS7 NAGS PIGA PARS2 CYC1 ACAD9 FADD CYFIP2 AARS1 TREX1 PMPCB MECP2 NTRK2 NDUFAF1 TWNK TGFB1 ND6 GRIN1 SLC25A1 SCN2A NDUFB3 CHD2 GRIN2D SCN3A UGT1A1 CLPB NADK2 GLDC CACNA2D2 SCN8A KCNA2 TSEN54 CPLX1 SCN1A NDUFA1 AMT NECAP1 WWOX FBLN1 GABBR2 CDKN2A TRNC TRNK CUX2 GABRA2 CYFIP2
Protein Mutations 1
A3243G
SNP 0