A New Therapy for Neurodevelopmental Mitochondrial Disorders

Project Summary Eight out of ten children with mitochondrial disorders die before three years of age. The most critical predicting factor of such a fatal outcome is the age of disease onset. Children who manifest the first symptoms during the neonatal or early infantile periods have a ten times higher risk of dying than those who present later.

Despite recent advances in prenatal diagnosis, there are no approved treatments for mitochondrial diseases during pregnancy. As a result, most children are born with severe malformations, mainly of the nervous system, rendering most postnatal therapies ineffective. We have identified a new drug to support

intermediary metabolism during pregnancy and postnatal periods in a mouse model of one of the most common human mitochondrial diseases: pyruvate dehydrogenase deficiency (PDHD). Approximately 80% of babies with PDHD are born with structural defects of the brain, including cortical dysplasia, hypoplasia of the corpus

callosum, and cerebellar atrophy, resulting in severe intellectual disability, intractable seizures, and short lifespan. To identify this treatment, we tracked glucose metabolism in vivo in a mouse model of PDHD to ascertain the metabolic pathways that are amenable to treatment. We found that the Krebs cycle is a

critical pathway. In contrast to the control brain, the activity of the Krebs cycle is partially sustained by the incorporation of non-glucose-derived substrates at several entry points throughout the cycle. A main entry point is succinyl-CoA. A singular characteristic of succinyl-CoA and its precursors is that they provide net carbons to

replace Krebs cycle intermediates that engage in biosynthesis. This finding is important because current treatments for PDHD do not support biosynthesis and the developmental processes that depend on it, including cell proliferation, migration, and myelination. We hypothesize that a specific precursor of succinyl-CoA could

represent a new therapeutic strategy to improve neurodevelopmental outcomes in this condition. To test this hypothesis, two independent aims are proposed: 1) To analyze how a specific succinyl-CoA precursor is metabolized in the PDHD brain; 2) To evaluate its therapeutic impact on neurodevelopmental outcomes in the

PDHD mouse model. The research proposed is significant because it aims to prevent, for the first time, neurodevelopmental deficits in PDHD and, by virtue, to improve the quality of life and life expectancy in this condition. This proposal is innovative because it will test a new drug to treat PDHD as early as the prenatal

stages. Our preliminary data indicate that the administration of this drug is safe during pregnancy in mice. Positive results from these studies may have important implications for patient care because the drug is already FDA-approved for human use and can be applied to other metabolic conditions in which brain biosynthesis is

impaired.