TESS Foundation Funded Research Projects
The Na+/Citrate Transporter In Human Neurons.
Anne Murphy, PhD and Ana M. Pajor, PhD
University of California San Diego
In this project, Dr. Pajor, Dr. Murphy and their teams will investigate the effect of loss of SLC13A5 expression on transport of citrate and succinate in cultured human neurons. They plan to study the metabolic and bioenergetic consequences of this loss to understand how it results in the development of epilepsy.
Drug Discovery in Slc13a5 Mutant Zebrafish.
Deborah M. Kurrasch, PhD
University of Calgary
Over the past funding period, Dr. Kurrasch and her team developed a zebrafish model that harbors a frameshift mutation in slc13a5. In the proposed project, she will continue testing this zebrafish model to screen a new repurposed drug library and further validate the drugs uncovered in these screens.
Creation Of Humanized Mouse And Fly Models Of SLC13A5 Mutant Syndrome To Determine The Cause Of Neurological Dysfunction And To Identify And Test Treatments.
Stephen L. Helfand, MD
In this project, Dr. Helfand and his collaborators aim to create a humanized mouse model in which a normal mouse SLC13A5 gene will be replaced by either a normal human SLC13A5 gene or a mutant human SLC13A5 gene. Dr Helfand has also created fly models of SLC13A5 and aims to study them further to pinpoint the physiological pathway that is affected due to SLC13A5 mutation. These mice and fly models will be instrumental in understanding how human SLC13A5 mutations cause neurological deficits and will be used to test and validate proposed treatments.
The Pajor Lab.
The main focus of the Pajor Lab is to understand the mechanism of sodium-coupled transporters, particularly the Na+/dicarboxylate cotransporters (NaDC) from the SLC13 family. A number of mutations have been identified in the NaCT transporter gene (SLC13A5) in patients with epileptic encephalography. The Pajor Lab explores what these mutations do to the function of NaCT. By studying the effects of these mutations, we may be able to identify a treatment for this disease.
SLC13A5 Bio-Bank at Stanford.
This project, spearheaded by Dr. Brenda Porter, creates a Bio-Bank of blood and skin samples of SLC13A5 patients and their parents. These blood and skin samples will be made available to researchers studying SLC13A5 and its role in epilepsy. Currently there are no animal models that recapitulate the neurological phenotype of SLC13A5. Ideally, the mechanisms underlying SLC13A5 mutations need to be studied in human patients and in their cells. Since neurons maintain the genetic profile of an individual, studying neurons derived from human induced pluripotent stem cells (hiPSC) is attractive as a method for studying neurons from SLC13A5 patients. A Bio-Bank is the first step in creating hiPSC and neuronal cell lines.
Baylor College of Medicine and Texas Children’s Hospital.
Dr. Brett Graham and Dr. Sarah Elsea are collaborating to screen and monitor metabolomic markers for SLC13A5 Deficiency and translate them into precision medicine. They have currently enrolled several patients with SLC13A5 mutations in a Triheptanoin drug trial. Triheptanoin, made by Ultragenyx, is intended to provide patients with medium-length, odd-chain fatty acids. Due to its odd-chain properties, triheptanoin is broken down into metabolites that replace deficient intermediates in the Citric Acid Cycle, a key energy-generating process that is likely disrupted by SLC13A5 mutations.