Department of Neurosurgery
Professor of Translational Neuroscience
Gene Expression; Gene therapy; Molecular and Cellular Biology; Molecular Basis of Disease; Neurobiology; Neuropharmacology; Transcription and Translation
The efforts in my lab are broadly directed at the translational research of neuroprotective/neurorestorative agents. Specifically, I am focused on the preclinical and clinical development of therapies used to prevent behavioral and cognitive deficits following traumatic brain injury (TBI) and stroke. Over 800,000 patients each year in the US suffer stroke and more than twice that number suffer TBI. Unfortunately there are currently no FDA approved therapies for TBI. TPA is the only therapy approved for stroke but is only applied in about 4% of stroke patients. Furthermore, while TPA is thrombolytic, it does not limit the cascade of pathology initiated by the original occlusion.
We have demonstrated that low dose methamphetamine is highly neuroprotective when administered as an acute treatment (within 12 hours after injury) following severe stroke or TBI. We have show that treatment with methamphetamine significantly improve cognition and functional behavior in rat models of these injuries. This effect is primarily mediated through the activation of a dopamine/PI3K/AKT signaling cascade and results in the preservation of primary neurons, and axons, as well as enhanced granule cell neurogenesis and white mater track remodeling. Furthermore, gene expression analysis suggests methamphetamine treatment significantly reduces pro-inflammatory signals and stabilizes the blood brain barrier.
These observations led us to further investigate the potential of low dose methamphetamine to reduce or prevent post-traumatic epilepsy. Using long-term video/EEG monitoring, we determined that methamphetamine treatment significantly reduces the incidence and susceptibility to post traumatic epilepsy/seizures after severe TBI in rats. This becomes quite relevant when one considers that many patients with post-traumatic epilepsy are pharmacoresistant. We are continuing to use the TBI model to investigate the causes of post-traumatic epilepsy and test novel therapeutics. In addition to single severe injury, we are also very interested in the effects of repeated mild TBIs. It has now been observed that multiple mild TBIs can cause clinical seizures in about 50% of rats. Therefore, we are also using this model to investigate the causes of post-traumatic epilepsy and potential therapeutic interventions.
We have now completed a phase I human trial of methamphetamine in healthy volunteers and are moving to conduct a phase IIa dose escalation safety study in TBI patients. In addition, we are currently using NGS to examine plasma miRNA changes as potential biomarkers and objective measures of activity to support the phase IIa study.
In addition to small molecules, my lab also is investigating the development of Adeno- associated virus (AAV) vector based gene therapy approaches to the treatment of CNS injuries such as post-traumatic epilepsy. Specifically, we are using recombinant AAV vectors to modulate targeted gene expression in a temporal, tissue-specific and cell type-specific manner within the CNS.