The Prosser Lab
Benjamin Prosser, PhD; Ingo Helbig, MD; and Beverly Davidson, PhD
University of Pennsylvania
“Targeting micro-RNAs to treat genetic epilepsies”
Supported by AES, The Cute Syndrome Foundation, and SLC6A1 Connect
Scientist Thesis Statement: Numerous genetic epilepsies arise from haploinsufficiency, the reduced expression of epilepsy associated genes. The Prosser lab hypothesizse that the expression of downregulated genes can be restored through antisense oligonucleotides (ASO) that specifically disrupt gene repression by microRNAs (miRs).
The Gray Lab
Steven Gray, PhD; Berge Minassian, MD; and Kimberly Goodspeed, MD
University of Texas Southwestern
SLC6A1 Syndrome associated with mutations in the SLC6A1 gene severely disables affected children. At the basic mechanism level, the brains of children lacking this gene cannot generate adequate energy for proper functioning of the brain. Unfortunately, there is neither cure nor treatment for the disease. In the present day and age, doctors can diagnose this easily, know its precise cause (missing SLC6A1 function), but have nothing to offer these children and families.
The goal of this project is to replace the missing SLC6A1 gene in the children suffering from its absence. The gene replacement is carried out using a special virus called AAV9. This virus is a safe virus that normally lives within us humans. The SLC6A1 gene is packaged in the virus, and the virus delivers the gene to brain cells.
As a first step, we need to show that this is feasible and safe in the mouse model of the disease, i.e. in mice likewise lacking the same gene. This pre-clinical work (mouse experiments) will entail:
· Establishing a colony of SLC6A1 deficient mice in our laboratory. This step is complete.
· Assessing for safe and efficacious delivery of the viral vector and the SLC6A1 cargo to the mouse central nervous system. This step is underway.
· Assessing the effectiveness of the treatment in the mouse. Specifically, we will test whether the brain energy metabolic defect that results from absence of SLC6A1 is corrected, at least in part, in the mice receiving the gene replacement. This step is underway.
Once we show that the treatment works, even if partially, in the mouse model of the disease, and does not cause harm, we will obtain permission from the Food and Drug Administration to initiate a human clinical trial. If successful, children and families afflicted with this terrible disease will no longer be told ‘ there is nothing I can do for you’, but instead be told, ‘ SLC6A1 deficiency, OK, here’s what we’re going to do…’
Dr. Berge Minassian
Pediatric neurologist Dr. Berge Minassian has special expertise in caring for patients with epilepsy, neurodegenerative diseases, and neurogenetic conditions. A physician-scientist, Dr. Minassian has spent much of his 20 years of research seeking the underlying genetic causes of epilepsy. He works closely with Children’s Medical Center Research Institute at UT Southwestern.
“I’ve been working to piece together the brain’s genetic underpinnings – to help us better understand both how the brain works overall and how faulty genes can lead to electrical problems in the brain in conditions such as epilepsy,” he says.
Board certified and fellowship trained, Dr. Minassian serves as Chief of Pediatric Neurology at UT Southwestern Medical Center and leads the Neurosciences Center at Children’s Health in Dallas.
“One of the main reasons I came to UT Southwestern was to develop a gene therapy program aimed at curing various types of epilepsy,” he says. “I really want to help make a fundamental difference in families’ lives by altogether eliminating the problem in as many cases as we can.”
He also serves on the faculty of the Children’s Health Epilepsy Center, which he notes is “one of the top centers of its kind in the country, if not the world. Everyone who works here does a fantastic job of caring for our patients.”
Dr. Steven Gray
Dr. Steven Gray earned his Ph.D. in molecular biology from Vanderbilt University in 2006, after receiving a B.S. degree with honors from Auburn University. He performed a postdoctoral fellowship focusing on gene therapy in the laboratory of Jude Samulski at UNC Chapel Hill. He is currently an Associate Professor in the Department of Pediatrics at the University of Texas Southwestern Medical Center.
Dr. Gray’s core expertise is in AAV gene therapy vector engineering, followed by optimizing approaches to deliver a gene to the nervous system. His major focus is in AAV vector development to develop vectors tailored to serve specific clinical and research applications involving the nervous system. These include the development of novel AAV capsids amenable to widespread CNS gene transfer. As AAV-based platform gene transfer technologies have been developed to achieve global, efficient, and in some cases cell-type specific CNS gene delivery, his research focus has also included preclinical studies to apply these reagents toward the development of treatments for neurological diseases. Currently these include preclinical studies for Rett Syndrome, Giant Axonal Neuropathy (GAN), Tay-Sachs, Krabbe, AGU, and Batten Disease, and have expanded into human clinical studies to test a gene therapy approach for GAN.
Dr. Gray has published over 50 peer-reviewed papers in journals such as New England Journal of Medicine, Molecular Therapy, Nature Biotechnology, Gene Therapy, and The Proceedings of the National Academy of Sciences. He also has 3 pending patents. His research is funded by the National Institute for Neurological Disorders and Stroke, as well as numerous large and small research foundations. Dr. Gray was recently recognized with the 2016 Healthcare Hero award by the Triangle Business Journal, and his work on GAN was featured in a story by the CBS National Evening News in 2015.
Dr. Kim Goodspeed
Dr. Goodspeed is board certified in pediatrics and neurology at UTSW, specializing in patients with neurodevelopmental conditions and other developmental disabilities. She is devoted to clinical research and understanding the natural history of rare disorders, and translational research to bring cutting edge therapies to our patients.
We have a ROBUST mouse model! SLC6A1 knockout mice are AVAILABLE via Jackson Laboratories and begin having noticeable tremors on Day 19! ASK US ABOUT OUR MICE!
SLC6A1 is a recently discovered pathogenic mutation and is only on 13% of panel testing, so the condition is very under-diagnosed.Dennis Lal’s genomics lab predict (unpublished, in review) 2.6 (CI:2.3-2.8) new SLC6A1 patients in 100,000 births, which translates to an incidence of about 1 in 38,000 births. In addition: