Date of Award
10-16-2023
Degree Type
Thesis
Degree Name
Master of Science (MS)
Department
Neuroscience
First Advisor
Kelly Langert
Abstract
Peripheral neuropathies encompass a range of painful and often disabling diseases that harm cells of the peripheral nervous system. A prominent feature of many peripheral neuropathies is demyelination and nerve function loss leading to sensory and motor degeneration. These conditions can be acquired or inherited; prevalent examples of each are Guillain-Barré Syndrome (GBS) and Charcot-Marie-Tooth (CMT) disease, respectively. Both diseases feature aberrant infiltration of leukocytes through the blood nerve barrier (BNB). It has been previously demonstrated that statin treatment attenuates disease in the rat experimental autoimmune neuritis (EAN) model by inhibiting GTPase-dependent immune cell infiltration across the BNB. However, relevant dosing of statins is associated with systemic toxicity including myopathy and rhabdomyolysis. Statins are potent inhibitors of HMG-CoA reductase and downstream products of the mevalonate pathway. Nitrogen-containing bisphosphonates and geranylgeranytransferase (GGT) inhibitors (GGTIs) are two classes of mevalonate pathway inhibitors that inhibit the enzymes farnesyl pyrophosphate synthase and GGT-1, respectively. In sequence, these enzymes control post-translational prenylation of GTPases that facilitate the release of a key inflammatory chemokine, CCL2. Interference at these points in the mevalonate pathway may provide a more specific, novel anti-inflammatory method. An immune cell-based targeted membrane vesicle delivery system provides advantages over systemic drug delivery. The natural targeting ability of immune cells toward inflamed nerves may be therapeutically harnessed by packaging mevalonate pathway inhibitors into nanovesicles derived from their plasma membranes. Targeted drug delivery avoids off target effects conferred by inhibiting the ubiquitous mevalonate pathway while increasing bioavailability and evading immune surveillance. The feasibility of such a system will be demonstrated by packaging GGTI-2418 into representative immune cell plasma membrane-derived vesicles.
Recommended Citation
Judy, Carolyn, "Investigating the Anti-Inflammatory Mechanisms and Therapeutic Potential of Mevalonate Pathway Inhibitors for Peripheral Neuropathy" (2023). Master's Theses. 4506.
https://ecommons.luc.edu/luc_theses/4506
