Pilot Study of Triheptanoin in Patients With Glucose Transporter 1 Deficiency Syndrome

Overview

Glucose transporter deficiency syndrome (Glut1-DS) is a form of pediatric epilepsy caused by a genetic mutation that disrupts the body's ability to process food from the child's diet into sugar (energy) needed to support brain function. Children with Glut1-DS experience seizures that are not controlled by anticonvulsant medications, as well as delays in cognitive and motor development. Currently, Glut1-DS is treated with the ketogenic diet, a high-fat, low-sugar diet that provides the brain with an alternate source of energy. Despite the significant improvement of seizures upon this diet, seizure control is incomplete in a majority of children, and they continue to experience problems with brain development. Our team of researchers and clinicians with expertise in metabolic diseases, neurology, pediatrics, biochemistry, and genetics believes that there is an opportunity to achieve CURE's goal of "No Seizures/No Side Effects" for children with Glut1-DS by investigating the use of a new treatment option that is designed to compensate for the underlying biochemical deficiency thought to contribute both to the seizures and to the impaired brain development associated with Glut1-DS. The proposed treatment involves incorporating a special type of oil, called triheptanoin, into the ketogenic diet as a way to make up for a specific biochemical deficit affecting kids with Glut1-DS that the standard ketogenic diet fails to address. Our goal is to do a pilot study to test the safety and effectiveness of this promising new treatment option in a small group of children with Glut1-DS.

BACKGROUND: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is a metabolic epileptic encephalopathy caused by defects in the cerebral glucose transporter GLUT1. It is characterized by infantile seizures refractory to anticonvulsants, deceleration of head growth, and delays in mental and motor development. Low brain glucose and subsequent energy deficiency is considered the major pathogenic factor causing seizures. The ketogenic diet (KD) is the only causal treatment available for Glut1-DS, and its therapeutic effect resides in its ability to provide an alternate source of energy for the brain. However, seizure control with KD is not complete in many patients and the long-term cognitive outcome is not optimal. Biochemically, these observations can be explained by a lack of energy for metabolic functions provided by pathways derived exclusively from glucose, which the alternate energy from the KD fails to supplement. HYPOTHESIS: We hypothesize that an anaplerotic agent adjunct to KD may be effective for controlling seizures and improving cognitive outcomes in children with Glut1-DS. Triheptanoin (C7) is a triglyceride containing the odd chain C7 (heptanoic) fatty acid, which occurs only in limited amounts in the natural diet. It improves the oxidation of acetyl CoA by the tricarbonic acid (TCA) cycle, leading to subsequent oxidative phosporylation by the electron transport chain to produce sufficient ATP for energy utilization. It also provides the TCA intermediates alpha ketoglutarate and oxaloacetate, which are important precursors for the neurotransmitters glutamate, GABA, and aspartate. Therefore, we expect these metabolic effects will enhance seizure control and/or neurodevelopmental function. SPECIFIC AIMS: We aim to generate preliminary evidence on 1) the safety, 2) the clinical, and 3) the biochemical effects of C7 as an add on therapy in GLUT1-DS patients with inadequate response to ketogenic diet. RESEARCH PLAN: To generate preliminary data and a better understanding of the precise biochemical mechanism of this novel treatment, we will conduct a pilot/proof of concept study using an open-label n-of-1 trial with 'an interrupted time-series before and after' design. We plan to enrol 3 Glut1-DS patients with incomplete seizure control, and the n-of-1 study design will help provide a distinct effectiveness estimate of C7 in each individual patient. As each participant acts as his/her own control, this design also supports an evidence-based, personalized medicine approach to treatment. SIGNIFICANCE: If successful, this personalized treatment approach may be extended to GLUT1-DS patients with other symptoms refractory to the KD, or those who cannot tolerate the diet, and ultimately will serve as a model for eliminating seizures and side effects in other medically refractory epilepsies. The data generated with this study will be essential to design future trials for a larger number of Glut1-DS patients to create high-grade evidence.