Delivery of Ubiquitin to Motor Neurons Using a Targeted, Sterically Stabilized Liposome Delivery System
Abstract
Background: We have identified that the cell s main garbage disposal machinery, the Ubiquitin Proteasome System, is a novel therapeutic target for the treatment of amyotrophic lateral sclerosis (ALS). In the current proposal, we aim to restore capacity of this system, which we believe to be severely compromised in ALS patients. We will achieve this by delivering the gene for ubiquitin (a fundamental component of this system) to motor neurons using a sophisticated targeted, drug delivery system. Objectives: To protect ALS motor neurons by developing a targeted nano drug delivery system for delivery of gene therapy to increase ubiquitin in the brain. Specific Aims: (1) Optimize gene delivery to motor neurons using a novel, non-toxic nano drug delivery system. (2) Compare our delivery system to existing gene therapy strategies in ALS mice. (3) Test the ability of our newly designed drug delivery system to deliver ubiquitin to the nervous system in mouse models of ALS and improve survival. We believe that increasing the amount of ubiquitin available in motor neurons will be protective regardless of the gene responsible for disease. Indeed, we believe that this strategy will be of benefit in all forms of ALS including sporadic cases. In addition, this project aims to design a therapeutic delivery system that increases the efficiency with which motor neurons are targeted. This will benefit ALS patients by increasing the amount of drug reaching motor neurons (other methods of gene therapy delivery in ALS have been disappointing thus far). In general, gene therapies require delivery using a modified virus, and once administered, the dosage cannot be altered. Conversely, our nano drug delivery system is safe (formulated using compounds found in the body) and can allow changes to individual patient dose as required. Further, our project has implications for any future drug development in ALS as we aim to develop a therapeutic delivery system that will increase the success rate of targeting any drug to motor neurons in the brain and spinal cord. This technology will not only be a method for delivering our targeted therapy but will be a vast improvement on previous delivery systems, providing an immediate impact on therapies that are currently under preclinical development or in clinical trial. The nano drug delivery system can be formulated to carry a wide variety of therapeutic cargoes. This will have a major impact on the types of drugs that can be delivered to motor neurons opening up many new avenues of therapy. In this context, and given that liposome delivery has already been validated for the treatment of other diseases such as cancer (i.e., Doxil is a clinically approved liposomal formulation in the United States for the treatment of sarcoma, ovarian cancer, and multiple myeloma), the translation of the findings from this project to humans would be immediate (2-5 years). In summary, this project aims to develop a novel therapeutic approach for the treatment of ALS. The next step towards translation will be to fully assess the safety/toxicity, organ distribution, and brain uptake properties of our lead drug formulation in clinically relevant animal models. This will ultimately guide the starting dose and schedule for human clinical trial after filing a fast track New Drug Application to the US Food and Drug Administration.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1610088
Entities
People
- Justin Yerbury
Organizations
- United States Army
- University of Wollongong