Targeted Liposomes for Treatment of ALS in Mutant SOD1-G93A Mouse Model

Open Access
- Author:
- Wiley, Nicholas J.
- Graduate Program:
- Neuroscience
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- June 03, 2008
- Committee Members:
- James Robert Connor, Thesis Advisor/Co-Advisor
- Keywords:
- amyotrophic lateral sclerosis
SOD1
liposome
minocycline
microglia - Abstract:
- Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurological disease characterized by the selective death of motor neurons. There is substantial evidence that degeneration is propagated by activated microglia and accompanying inflammation. To this end, several therapeutic agents have aimed to curb microglia activation, albeit with little success. The present study aimed to increase site-specific concentration and thus drug efficacy with the use of an osmotic intracerebroventricular (ICV) pump by delivering minocycline contained in liposomes with a targeting moiety specific to microglial cell surface markers. It was hypothesized that attenuating microglial activation would delay the kinetics of disease progression. The potential therapeutic efficacy of this approach was shown in both in vitro models with mouse microglia-derived BV-2 cells as well as an in vivo model involving mutant SOD1G93A mice. The in vitro results indicate that targeting the TLR4/LPS complex significantly increases (p<0.05) the uptake of drug by 29% compared to non-targeted liposomes. In the SOD1G93A mouse model of ALS, both targeted and non-targeted minocycline treatment significantly increased (p<0.05) latency to endpoint stages compared to control mice receiving no treatment. Although, targeting treatment to microglia only slowed later disease progression with statistical significance. The results of this study provide evidence for a greater role of microglia in disease progression, and not disease onset, and suggests targeting microglia provides a viable therapeutic target for slowing progression after initial clinical diagnosis.