Joshua T. Dearborn, PhD

• Lysosomal storage disorders
• Mouse behavior
• Cannabidiol for the treatment of seizures
• Gene therapy
• Enzyme replacement therapy

I am a behavioral neuroscientist with training in molecular biology. My research interests revolve around the neurobiology and etiology of neurodevelopmental disorders. I have a strong background in the application of rodent models in behavioral assays to investigate the neurobiological mechanisms related to behavioral disruptions observed in psychiatric disorders. I am interested in determining the underlying mechanisms leading to both central and peripheral defects associated with lysosomal storage diseases (LSDs) and using that information to develop effective therapies for this class of disease. I am inspired by the lack of clear understanding of the molecular- and circuit-level neuropathology mediating the symptoms of neurodevelopmental disorders such as infantile neuronal ceroid lipofuscinosis (INCL).

My current projects address multiple facets of neurodevelopmental disease. I am studying the effects of cannabinoids on the seizure phenotype in the mouse model of INCL. The use of cannabinoids as a treatment for human seizure disorders continues to gain popularity despite a conspicuous lack of basic science evidence for the strategy. My aim is to fill that void by administering cannabidiol to INCL mice, both acutely and chronically, and measure the effect on seizures via continuous EEG monitoring.

I also use gene therapy strategies to measure their ability to prevent and correct LSDs, asking questions about vector promoters and enhancers, routes of delivery, and timing of treatment. It has been shown time and again that using a viral vector with the strong CBA promoter-enhancer element results in hepatocellular carcinoma (HCC) later in life via various undesirable integration events. I created a novel vector with a moderate-strength promoter and no enhancer to deliver a functional copy of the necessary gene to INCL mice and hopefully avoid the development of HCC. Germane to this research are questions about route of administration and timing of delivery. I am testing the efficacy of gene therapy and enzyme replacement therapy via intracranial, intrathecal, and intravenous delivery in neonatal and adult INCL mice. Notably, in collaboration with pediatric surgeons at St. Louis Children’s Hospital, I am researching the effects of applying gene therapy, enzyme replacement therapy, and bone marrow transplant in utero to embryonic mice. I am applying these in utero strategies to both INCL mice and the mouse model of mucopolysaccharidosis type VII.

My expertise really lies in behavioral assays to measure effects of disease and treatment in rodent models of human disorders. In studying LSDs such as INCL and MPSVII, one of the most commonly applied behavioral measures is the rotarod; it is a well-established apparatus that evaluates motor coordination and motor learning. Within the LSD field, however, there is disparity in how the apparatus is used. I seek to establish a protocol for measuring motor coordination in LSD mice in a more uniform manner, thus allowing more appropriate comparison of results between labs. In addition, I am currently examining the mouse model of Krabbe disease, another LSD, to establish an in-depth characterization of the development of gait abnormalities in this disease.