476226 Towards Treatment of Neurodegenerative Disorders through Nanoparticle Mediated Enzyme Replacement Therapy
Approximately 1 in 5,000 to 8,000 children are born annually with a lysosomal storage disease (LSD). Current treatment of LSDs, called enzyme replacement therapy (ERT), involves weekly to monthly intravenous (IV) infusions of missing endogenous enzymes. While ERT has proven effective in LSDs without central nervous system (CNS) involvement, the brain has remained untreatable due to the presence of the blood-brain barrier (BBB), which prevents passage of 98% of small molecule drugs, including enzymes, from the blood into the brain. Patients with neuropathic LSDs, which account for 50-70% of diseases in this category, present with severe CNS degeneration, ataxia, and premature death, with no treatment available on the market. The disease of focus, GM1 gangliosidosis, causes premature death between the ages of two and four with no hope available for parents of patients. Encapsulating enzyme into polymeric vesicles made up of polyethylene glycol and polylactic acid, called polymersomes, facilitates the transport of this missing enzyme into the brain through IV injections, effectively extending ERT therapy to the brain for the first time.
The missing enzyme in GM1 gangliosidosis, β-galactosidase (βgal) was loaded into polymersomes at a high efficiency, with 0.08 ± 0.03 mg βgal/mg polymersome, while maintaining its activity at 452 ± 82 a.u. Release of βgal was doubled over 6 hours when loaded polymersomes are placed into citrate buffer (pH=4.1) when compared to HEPES buffer (pH=7.4), indicating increased enzyme release expected in the lysosome. Attachment of ApoE was confirmed with an increase in polymersome diameter to 194.4 ± 3.5 nm and an increase in protein content from 0.06 ± 0.11 mg/mL to 1.03 ± 0.71 mg/mL. GM1SV3 cells, an immortalized cell line from felines with GM1 gangliosidosis, present low density lipoprotein receptors (LDLR) on the surface, as shown in confocal microscopy, indicating that they are a good model for ApoE mediated delivery through the BBB. ApoE increases the uptake of polymersomes into GM1/SV3 fibroblasts when compared to unlabeled control polymersomes.
My work highlights our ability to create polymersomes capable of protecting βgal in the blood stream, targeting the nanocarrier to the BBB, and after transcytosis, releasing βgal in the lysosome of neural cells. This combination of ERT and nanotechnology, demonstrating the capability of our carrier to transport enzymes to the brain while maintaining their activity, will create a paradigm shift in the treatment of CNS disease, providing treatment for currently untreatable and fatal diseases like GM1 gangliosidosis.
As an instructor, it is my privilege to shape future engineers and motivate them to contribute to the direction of the field. I have demonstrated my ability to teach in both a classroom and laboratory setting through Teaching Assistant (TA) experience in Introduction to Chemical Engineering, Senior Design Lab, and Principles of Chemical Engineering at Auburn University. Though each experience was unique, I learned the universal importance of flexibility when teaching a course. It is necessary to constantly evolve in order to service the needs of your students as they progress and their understanding of the material matures.
I am passionate about inspiring students to excel in the chemical engineering field and excited to take on any chemical engineering course. Instruction of Thermodynamics, Principles of Chemical Engineering, Transport Phenomena, and Biomedical Engineering aligns closely with my strengths. My previous research experience developing novel nanocarriers for drug delivery applications and working in both the Chemical Engineering and Veterinary Medicine departments has prepared me for the integration of biomedical projects and assignments into any course, as well as the design of a Drug Delivery course. It is my goal as an educator to provide every student with the opportunity to engage in their own learning through flexible techniques. I want my students to leave the classes I teach with an understanding of the way in which the knowledge they have gained can contribute to the direction of the chemical engineering field.
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