Rabbit Model for Gliomas
Human glioma models have been produced in murine models but have not yet been consistently done in a larger animals. The primary objective of this collaborative project with Dr. Frederick Lang, Chair of Neurosurgery at MD Anderson, is to create a rabbit model of human glioma by xenotransplantation of cultured human glioblastoma cells into immunosuppressed New Zealand white rabbits.
The establishment of tumors in animals by xenografting tumor material, mostly in the form of established cell lines, has been highly valuable in the search for mechanisms that determine tumor formation, growth and progression. In general, intracerebral inoculation of human glioma cell lines in immunosuppressed animals leads to the development of tumors with typical growth characteristics.
The advantages of cell line-based models are 1) good reproducibility with regards to engraftment rate and 2) reliable growth and disease progression. Most often, human cell line-derived xenografts also display some levels of angiogenesis. This method for human glioma modeling in rabbits can provide the foundation to test novel treatment strategies, including intra-arterial therapeutic agent delivery.
Comparison of Endoscopic-Assisted Mechanical Thrombectomy with Standard Mechanical Thrombectomy in Vessel Occlusion Model
Currently, all modern neuroendovascular techniques rely on fluoroscopy and iodinated contrast to guide the positioning and deployment of devices. Radiation-induced complications of fluoroscopy include skin burns and hair loss, which can occur at doses as low as 3 Gy. Furthermore, contrast-related nephropathy has been reported to occur in approximately 20-30 percent of patients with pre-existing renal disease and up to 5 percent in low-risk individuals. Lastly, indirect visualization in cases with difficult anatomy can contribute to malpositioned devices, leading to thromboembolic and hemorrhagic complications.
Starting out as a "proof of concept" study with Vena Medical, we have established promising and innovative research based on a vessel occlusion model in swine. Our overall goal is to improve recanalization and reduce complications with mechanical thrombectomy (MT). We have recently developed a novel microangioscope that offers both high-quality optics and the miniaturization necessary to navigate in small intracranial vessels. In addition, we have demonstrated in a large animal model that we can clearly visualize arterial branch points, differentiate different kinds of thrombus, and perform MT under direct visualization with our microangioscope. Based on these experiments, we believe direct visualization with microangioscopy during MT can improve the efficacy and safety of the procedure. This transformative “endoscopic-assisted mechanical thrombectomy” (EMT) could be both safer and more efficacious than the current MT performed under fluoroscopy using iodinated contrast.
Intravenous Infusion of MCB-613 in Stroke Model
Stroke is the fifth leading cause of death and the leading cause of adult disability with an estimated cost of near $70 billion in the United States. A stroke is an interruption of the blood supply to any part of the brain, which can lead to brain cell death causing a myriad of symptoms, ranging from extremity weakness to death.
MCB-613 is a potent small molecule stimulator of SRC (steroid receptor coactivator) and has been shown to stimulate SRC-1, SRC-2 and SRC-3. In preliminary studies, MCB-613 has been shown to decrease the severity of myocardial infarction. In these studies, MCB-613 was shown to be highly concentrated in the brain parenchyma due to its lipophilic properties.
If proven to be effective, considering the similarity between myocardial infarction and stroke, it would be an important neuroprotective agent given at the onset of stroke-like symptoms thereby increasing the therapeutic window for effective treatment. At the moment, there are no effective neuroprotective treatments for stroke patients. The only medical treatment in acute ischemic stroke is tPA, which works by dissolving the clot and improving blood flow but must be given within four and a half hours in eligible patients.
This project is a collaboration with Dr. Bert O'Malley, Chancellor at Baylor College of Medicine, Division of Molecular and Cellular Biology. Our first aim is to perform a preliminary experiment to demonstrate that MCB-613 has a positive therapeutic effect in the MCAo model. The purpose of this project is to (a) test the neuroprotective effects of MCB-613 on an established murine middle cerebral artery occlusion (MCAo) model and (b) develop an effective treatment regimen to lessen the negative impact of MCAo.
Development of a Wireless Endovascular Nerve Stimulator for Treatment of Refractory Neuropathic Pain
Neuropathic pain is a disabling pain syndrome affecting approximately 7 to 10% of the US population and contributing to nearly 40% of all patients with chronic pain. This devastating disorder can lead to increased opioid usage as well as sleep disturbances, anxiety, and depression. In the last several years research has shown that electrical stimulation of central and peripheral nervous system targets is an effective treatment for reducing pain and an effective alternative to opioid therapies. The most commonly targeted structures include the spinal cord and the dorsal root ganglia (DRG). However, adoption of bioelectronic pain therapies has been limited by the risks (actual and perceived) associated with a large implanted device and the associated surgery.
This collaboration with Dr. Jacob Robinson at Rice Engineering and Dr. Sunil Sheth at UTHealth Neurology proposes a minimally invasive technology for electrical stimulation of the DRG to treat pain. Unlike commercially available DRG stimulators that require surgery to implant a battery pack and pulse generator, we will create wirelessly powered nerve stimulators that are small enough to be placed on stents and delivered within the blood vessels adjacent to the DRG. By eliminating the implantable pulse generator and leads, this transformative “endovascular nerve stimulation” (EVNS) technology will reduce the actual and perceived risks associated with nerve stimulation therapies for pain in five major ways:
- Less invasive device delivery.
- Elimination of device failures due to lead migration, resulting in more predictable outcomes.
- Reduced risk of infection by eliminating the implanted generator.
- More precise placement and access to distal nerve segment beyond the DRG.
- Implantation in patients who have undergone prior spine surgeries.