Rabbit Model for Human Gliomas
Human glioma models have been produced in murine models but have not yet been consistently done in a larger animal model. The primary objective of this experiment is to create a rabbit model of human glioma by xenotransplantation of cultured human glioblastoma cells into immunodeficient New Zealand white rabbits.
The establishment of tumors in animals by xenografting tumor material, mostly in the form of cell lines, neurospheres and biopsies, has been highly valuable in the search for mechanisms that determine tumor formation, growth and progression. In particular, with the advent of immunodeficient animals, important insight has been obtained relating to the growth of human tumors within the central nervous system. In general, intracerebral inoculation of human glioma cell lines in immunodeficient 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 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 quickly established promising and innovative research based in 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 trans-formative “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 that has been used to disrupt cancer cell homeostatic dependence on SRCs. In preliminary studies, MCB-613 has been shown to decrease the severity of myocardial infarction leading to decreased tissue damage with and the loss of cardiac function. 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 three hours of onset or four and a half hours in eligible patients.
In this collaboration with Dr. Bert O'Malley and his lab, 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.
Treatment Effect of Glioblastoma with MCB-613
Glioblastoma (GBM), the most common and aggressive primary tumor in adults, effects approximately 15,000 people each year, and exhibits a mean survival time of only 14.6 months. The current standard treatment for GBM consists of a combination of surgery and radio-chemotherapy. The infiltrating properties of GBM and the resulting seeding of distant tumor cells often makes surgical resection alone insufficient, while radiotherapy alone is also limited due to the inherent radioresistance of GBM cells.
With chemotherapy, the major cause of failure is poor delivery of the therapeutic agents across the blood-brain barrier (BBB). This necessitates the use of high plasma drug concentrations, which expose patients to frequent and severe adverse effects. To circumvent the BBB, clinicians often opt for direct intratumoral injection of chemotherapy agents, which often leads to backflow, leakage, and a lack of initial distribution of the therapeutic agent. Because of this, there is an ongoing effort to refine current treatments and develop novel therapies.
MCB-613 may prove to be an effective treatment for GBM. It is a potent small molecule stimulator of SRC (steroid receptor coactivator), and has been shown to stimulate SRC-1, SRC-2, and SRC-3 that has been used to disrupt cancer cell homeostatic dependence on SRCs. In addition, MCB-613 is proven to be highly concentrated in the brain parenchyma due to its lipophilic properties, meaning its freely crosses the BBB. In preliminary in vitro studies, MCB-613 and its derivatives has been shown to decrease the cell viability in most cancer cell lines, especially U87. In most cell lines, the EC50 is approximately 5-6 micromolar, while in U87 cells, it is 3 micromolar indicating that U87 cells are fairly sensitive to MCB-613 and its derivatives.
In this collaboration with Dr. Bert O'Malley's lab at BCM and Dr. Fredrick Lang's lab at MD Anderson, we hope to show MCB-613 to be effective, and considering the effectiveness in the in vitro studies, it would be an ideal treatment for GBM and other cancer cell lines.
Rabbit Model For Retinoblastoma
Retinoblastoma is the most common primary intraocular malignancy in children affecting one in 20,000 children worldwide with 250 to 300 new cases reported in the United States each year.
Since clinical trials for retinoblastoma are difficult when compared to more prevalent cancers, development of animal models is essential for evaluating therapies. Over the last 10 years, intra-arterial chemotherapy has been described in treatment of children with retinoblastoma with promising results. However, the treatment technique and chemotherapy utilized varies highly between different institutions without consensus.
Use of up to three simultaneous medications have been described. The toxicity, efficacy and effects of combining the chemotherapy agents have not yet been explored in an animal retinoblastoma (RB) model. We anticipate that the data gathered in this intra-arterial rabbit retinoblastoma model will improve our understanding of intra-arterial treatment of retinoblastoma. If successful, this proposal will enable us to improve retinoblastoma treatment and develop and test new therapies in the future.
Wireless Endovascular Neural Stimulators For Minimally Invasive Treatment of Depression
Neural stimulation to treat depression presents a number of opportunities to improve the state of patient care. In particular, neuromodulation can have less off target effects compared to pharmaceuticals that are distributed throughout the body. Furthermore, electronic therapies do not require regular oral administration, which alleviates the challenge of ensuring that patients regularly take their prescribed medication. Finally, electronic therapies have the unique advantage of rapidly adapting stimulation based on real-time feedback to enable accurate regulation of a patient’s mental state using a “closed-loop” system with both stimulation and recording capabilities.
To realize widespread patient adoption of these bioelectronic therapies, however, it is critical to minimize the invasiveness and risks associated with implantation of neural stimulators. One promising approach is to introduce wireless stimulation and recording devices through the vasculature; however, there are limited technologies capable of wireless delivery of power and data to these tiny neural stimulators. Dr. Robinson and his engineering lab at Rice University have recently developed a new method to power bioelectronic implants using magnetoelectric (ME) materials that can be miniaturized to smaller than a grain of rice and powered externally by magnetic field coil.
This collaboration of BCM Neurosurgery, Rice Engineering and UTHealth Neurology will develop wireless magnetoelectric stimulators that can be integrated into a commercial stent and delivered through the vasculature to the central and peripheral nervous system. This transformative “endo-vascular neuro-stimulation” (EVNS) technology would be both safer and less invasive than current neuromodulation technology. While we focus the application of this technology toward depression, a successful demonstration of EVNS would provide as a platform for treating other mental health disorders.
Our two aims will provide the preliminary data needed to pursue wireless EVNS for minimally invasive bioelectronic treatment of mental health disorders including depression. In addition, we envision future work will enable to wirelessly EVNS technologies capable of both stimulating and recording neural signals to enable closed-loop treatments of mental health disorders.