Event-Triggered Gene Therapy for ALS: Smart Release of Therapeutics in the Brain
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown cause. Clinically, it is characterized by a rapid and progressive loss of motor neurons in the brainstem, spinal cord, and motor cortex resulting in muscle atrophy, weight loss, and paralysis leading to respiratory failure and death within 3 years of onset. It is believed that the activation of the immune system in ALS has significant contribution to the harmful processes that lead to the loss of muscle innervation and body paralysis. This is a complex process initiated by harmful processes such as the inflammation initiated by the proliferation and migration of inflammatory cells in the spinal cord and the brain, that release harmful proteins that damage the motor neurons that control the muscle contraction. Our proposal will focus on special enzymes called proteases that digest proteins and change the cellular environment surrounding the motor neurons in the spinal cord and the brain. Many of the pathological events in the spinal cord and the brain can be traced to the local pro-inflammatory processes that trigger several downstream mechanisms including the activation of proteases, enzymes that cleave proteins in and around the cells of the brain. We propose a strategy to develop transmembrane proteins that can be delivered to the spinal cord and the brain, specifically designed to release therapeutic proteins at the sites affected by the disease, after being cleaved by proteases that are activated during ALS. Our team has developed a way to change these proteases so that instead of being harmful they can now release therapeutic proteins. Once inserted into the cell membrane of spinal cord and brain cells, these sensors can be activated by the injury, to release therapeutics in the spinal cord and the brain to avert loss of motor neurons and thus to slow or even prevent the progression of ALS. Considering the significant personal, medical, and socio-economic impact of neurodegenerative diseases such as ALS, there is a pressing need for novel treatments. Our goal is to develop a powerful, prophylactic and locally acting, treatment to enable cells to release their own anti-inflammatory proteins to prevent the damage and loss of motor neurons. It is important that the therapeutic proteins are only released when and where they are needed to minimize any systemic side effects. We plan to develop ways to make these proteases to release therapeutic agents only at the hot-spots -- when and where a damaging inflammatory event occurs in the brain and spinal cord. This strategy can be further applied as a prophylactic treatment for patients with other neurodegenerative diseases including: Frontotemporal Dementia, Alzheimer s, and Parkinson s disease, Multiple Sclerosis, traumatic brain and spinal cord injury, stroke, and Age-related Macular degeneration.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310181
Entities
People
- Max Cynader
Organizations
- United States Army
- University of British Columbia