Neuron-Targeted Caveolin Gene Therapy Route of Administration to Treat ALS
Abstract
Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig s disease, is a progressive neurodegenerative disease resulting from loss of motor nerve cells (a.k.a. neurons) in the brain and spinal cord. ALS symptoms include diffuse muscle weakness, muscle loss, uncontrolled muscle contraction (a.k.a. spasticity), and paralysis, and short life expectancy (2-5 years). One approach to combat ALS is to deliver pro-survival growth factors to prevent loss of these motor neurons, yet this is dependent upon expression and the proper cellular localization of key protein receptors that in turn bind these growth factors. Our group has shown that when we over-express a scaffolding protein called caveolin (i.e., Cav, which is analogous to a coat hanger) specifically in neurons, these growth factor receptors move to the membrane of neurons, which allows them to bind these pro-survival growth factors. The goal of the current project is to deliver a vector that contains the genetic material for Cav, with selectivity to only increase Cav expression in neurons within the brain and spinal cord of ALS rodents. The objective is that delivery of this vector in combination with drugs that stimulate these growth factor receptors (i.e., agonists) will protect motor neurons in the brain and spinal cord of early on-set, moderate on-set, and late-stage ALS rodents as well as regenerate motor neurons in late stage ALS rodents (a.k.a. functional neuroplasticity). If proven successful in ALS rodent models, we will then generate large animal (pig) good manufacturing practice (GMP) safety data to define the optimal gene-containing vector dose which can be used for spinal cord delivery in human ALS patients (approximately 2 years). Subsequently, we will then design preclinical large animal safety studies and future clinical protocols to use spinal cord vector delivery to treat late- and early-stage ALS patients (approximately 3-5 years). Our ultimate objective is that this potential novel therapeutic approach will improve neuro-muscular function and strength, and extend life expectancy in both early- and late-stage ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210154
Entities
People
- Brian Head
Organizations
- United States Army
- University of California, San Diego