Grants & Research Studies

New research tool for the SLC13A5 community.

Geoffrey Chang, PhD
University of California San Diego

Dr. Chang and his team (UCSD) received an infrastructure grant to develop nanobodies—a key tool used to recognize the NaCT protein. Nanobodies can help identify when and where NaCT is found in the body, in which specific cells, and within a cell.

This project is an Infrastructure Project.

Research and further development of a cellular disorder model for SLC13A5.

Gaia Novarino, PhD and Carsten Pfeffer, PhD
Institute of Science and Technology Austria and Neurolentech

Dr. Novarino (IST Austria) and Dr. Pfeffer (Neurolentech) received follow-up funding to continue their research on patient-derived cell culture models of SLC13A5 Citrate Transporter Disorder. They are using these models to investigate an electrophysiological phenotype, as well as identify biomarkers and disease model pathologies.

This project is Follow-up Funding from Dr. Novarino’s 2018 Research grant.

Structural basis of the G219R mutations in SLC13A5 Epilepsy.

Da-Neng Wang, PhD

NYU School of Medicine

Dr. Wang and his team received follow-up funding to investigate the structure of the SLC13A5 Citrate Transporter Disorder mutant protein.

This project is Follow-up Funding from Dr. Wang’s 2018 Research grant.

SLC13A5 Deficiency Natural History Study.

Brenda E. Porter, MD, PhD, Co-PIs: Judy Liu, MD, PhD, Kimberly Goodspeed, MD

Stanford University, Brown University, University of Texas Southwestern

Dr. Porter is the lead PI of the multi-site SLC13A5 Deficiency Natural History Study. The goal of this study is to characterize SLC13A5 Deficiency throughout the course of the disease, identify potential biomarkers that correlate with disease severity, and broaden our understanding of SLC13A5 Deficiency. The Natural History Study is critical to prepare for clinical trials. This study has three parts: an in-person study, a remote study, and a digital study. For more information on the NHS, check out our website here.

This project is a Sponsored Research Project.

Gene Therapy for SLC13A5 Deficiency.

Rachel Bailey, PhD

University of Texas Southwestern

Dr. Bailey received funding to continue the development of a gene therapy for SLC13A5 Deficiency. She continue to investigate the gene therapy in a mouse model of SLC13A5 Deficiency, studying safety, efficacy, and toxicity of the gene therapy.

This project is Follow-up Funding from Dr. Bailey’s 2018 work on SLC13A5 Deficiency gene therapy development.

SLC13A5 Patient-derived Cellular Models for the Identification of Biomarkers and Drug Screening Strategies.

Gaia Novarino, PhD

Institute of Science and Technology Austria

We will develop cell culture models based on SLC13A5 patient-derived induced pluripotent stem cells that recapitulate disorder pathophysiology. These models are particularly suited to address early developmental brain pathologies. Combining single-cell transcriptomics, cellular and network electrophysiology as well as morphology we will identify pathophysiological changes between control and patient-derived cell culture models that will help understanding pathology mechanisms and identify biomarkers. Experiments for biomarker identification will be designed to allow straightforward application for medium to high-throughput drug and genetic screening assays. We believe this approach will identify SCL13A5 disorder pathology relevant biomarkers and disorder mechanisms which will be directly applicable to search for pharmacological treatments.

This project is a Research Grant.

Progress:

• Dr. Novarino developed a patient-derived cell culture model of SLC13A5 Citrate Transporter Disorder and is characterizing the phenotype.

Screening small molecules for the activation of NaCT mutants in SLC13A5 Deficiency.

Da-Neng Wang, PhD

NYU School of Medicine

SLC13A5 Deficiency is caused by mutations in the SLC13A5 gene. This gene encodes a sodium-driven citrate transport protein named NaCT. Disease-causing mutations abolish the uptake of citrate in neurons of the brain. We plan to develop a simple and efficient screening platform to search for small molecule activators that can rescue the mutants’ citrate transport activity.

This project is a Research Grant.

Progress:

• Dr. Wang and his team published the cryo-EM structure of NaCT in the journal Nature (Saur et al. 2021). This will be useful to identify how potential drugs may change the protein function.

Gene Therapy for SLC13A5 Deficiency.

Rachel Bailey, PhD

UT Southwestern Medical Center

Current treatment for SLC13A5 deficiency is limited to symptomatic palliative care and there remains an urgent need for an effective treatment that targets the cause of the disease. Gene therapy is one of the emerging strategies for the treatment of inherited disorders like SLC13A5 deficiency by delivering therapeutic genes directly to a patient’s cells in place of drugs or surgery. The proposed research will test a gene therapy approach in mice with SLC13A5 deficiency. A very similar gene therapy approach is currently being tested in humans with Giant Axonal Neuropathy. Results from the studies under this proposal could eventually allow the translation of this approach into a human treatment.

This project is a Research Grant.

Progress:

• The results of these studies are promising and Taysha Gene Therapies is now using this model in preclinical studies to develop a gene therapy for SLC13A5 Citrate Transporter Disorder (TSHA-105).
• TSHA-105 received rare pediatric disease and orphan drug designations.

SLC13A5 Deficiency Neural Precursor Cell development.

Toshihiko Ezashi, PhD, DVM

University of Missouri

Dr. Ezashi developed SLC13A5 neural precursor cells (NPCs) differentiated from patient-derived iPSCs.

This project is an Infrastructure Project.

Progress:

• These NPCs are available upon request.

Patient-derived iPSCs and parental controls.

Adriana Beltran, PhD

University of North Carolina

The goal of this project is to develop induced Pluripotent Stem Cells (iPSCs) from SLC13A5 Epilepsy patients, as well as iPSCs from parents. The development of these tools will provide a valuable resource for the SLC13A5 research community.

This project is an Infrastructure Project.

Progress:

• There are eight iPSC lines available upon request. These include 4 patient-derived lines, 1 isogenic control line, and 3 parent-derived lines.

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.

This project is a Research Grant.

Progress:

• Current preprint of “NaCT (SLC13A5) facilitates citrate import and metabolism under nutrient-limited conditions” is available on bioRxiv.org.

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.

This project is a Research Grant.

Progress:

• Kurrasch and her team have created zebrafish mutants and completely initial characterization of mutant phenotypes.

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

Brown University

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.

This project is a Research Grant.

Progress:

• Humanized mouse is currently undergoing characterization at Brown University.

Vector creation for SLC13A5 Gene Therapy.

Steven Gray, PhD

University of North Carolina

The goal of this mini-grant was to determine whether SLC13A5 Epilepsy is a suitable candidate for gene therapy. This mini-grant focused on the development of a vector for the SLC13A5 gene.

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.

Progress:

• Pajor has retired and joined the TESS Science Advisory Board. She helps build our scientific network, reviews scientific grants and papers, and shares her in-depth knowledge.

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 (iPSC) is attractive as a method for studying neurons from SLC13A5 patients. A Bio-Bank is the first step in creating iPSC and neuronal cell lines.

Progress:

• Patient-derived iPSCs and neural precursor cells (NPCs) have been developed and available for use.

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.

Progress:

• The researchers are currently putting together a publication to share the results of this study with the scientific community.