Metabolic Solutions is providing efficacy endpoint assays for rare disease and gene therapy treatment trials. Stable isotope tracers can be used in both pre-clinical and clinical studies to monitor specific biochemical pathways and provide evidence of restored enzyme activity. The following applications can be monitored using validated assays:
Urea Cycle Disorders such as ornithine transcarbamylase (OTC) deficiency
We can quantitatively determine urea synthesis rates using sodium heparin plasma specimens, collected after the oral ingestion of [1-13C]sodium acetate (Yudkoff et al). After establishment of a baseline rate of ureagenesis, an evaluation of changes in the ureagenesis rate in patients with OTC deficiency following gene therapy treatment can be performed. The ureagenesis assay provides a direct evaluation of the functional performance of the urea cycle, protecting patient safety with an additional parameter beyond ammonia and amino acid profile monitoring to aid in the determination of which patients are eligible to undergo modifications of baseline disease management during the clinical trial.
Ureagenesis requires the measurement of 13C-urea enrichment and urea concentration. Small plasma sample volumes (25-50 uL) are used so studies can be performed in both pre-clinical (rodent) or clinical (pediatric or adult) trials.
Phenylketonuria (PKU) Treatment Trials
Phenylketonuria (PKU) is a rare inherited disorder caused by a defect in the phenylalanine hydroxylase (PAH) gene. This defect results in high phenylalanine levels in blood. The direct measure of PAH activity can be assessed with the stable isotope tracer 1-13C-phenylalanine administered orally (Turki et al). The carbon-13 on the carboxyl part of phenylalanine is metabolized and excreted as breath 13CO2. Breath samples are a non-invasive way to monitor PAH activity following gene therapy to restore this enzyme activity. The functional assessment of PAH activity over 60 minutes can be used as an endpoint assessment to monitor PKU treatment.
Methylmalonic Acidemia Treatment Trials
Methylmalonic acidemia (MMA) is caused by a defect in the gene coding for the mitochondrial enzyme methylmalonyl-CoA mutase (MMUT). MMUT enzyme is essential for the oxidation of amino acids, odd-chain fatty acids and cholesterol. As discussed by Manoli et al, propionate oxidative capacity, as measured by the 1-13C-propionate breath test, predicts disease severity and clinical outcomes. The propionate breath test can assess the therapeutic effects of genomic therapies for MMA.
Other Rare Disease Endpoints utilizing Stable Isotope Breath Testing
- Fatty acid Oxidation Disorders
- Maple Syrup Disease
- Tyrosinemia
- Galactosemia