Platelet-Derived Extracellular Vesicles to Restore Neurovascular Integrity in ALS
Abstract
Critical Need for ALS Treatment. Amyotrophic Lateral Sclerosis (ALS) is a neurological disease that is driven by the death of nerve cells in the brain and spinal cord. ALS is prevalent in both men and women who are 55 years or older, military Veterans, or may have had prior brain injuries or infections. Initially, patients with ALS experience muscle weakness or stiffness and eventually progress to a loss of voluntary muscle movement, including chewing, walking, talking, and even breathing. Currently, there are no effective treatments to stop the disease from progressing. Most people with ALS die from respiratory failure within 5 years of diagnosis. Recently, it was discovered that the barrier between the circulating blood and the nervous system (including the brain and spinal cord) breaks down very early in ALS. In fact, this breakdown occurs even earlier than the death of nerve cells. The barrier between the blood and nervous system is made of a semipermeable border of cells called endothelial cells. This barrier is essential for maintaining healthy brain and spinal cord tissues and preventing the entry of unwanted particles into the nervous system where nerve cells reside. We have demonstrated that platelet-derived extracellular vesicles (PEVs), which are very small particles secreted from platelets, can repair damaged endothelial cells and improve barrier function. In this project, we will test PEVs in animal models of ALS to determine whether it can reduce or stop nerve cell death and disease progression by repairing the damaged blood-nervous system barrier. Results generated from this project will lay the groundwork for clinical trials to determine whether PEVs can enhance quality of life and potentially help ALS patients survive longer. Potential Benefits and Risks of PEVs. Therapy using platelet transfusion has been successfully and safely used in many clinical trials and hospital setting. PEVs are very small particles that are naturally secreted from platelets and offer additional benefits to platelets. For example, PEVs are easily soluble in saline, can be stored at low temperatures for extended periods of time, and are easily transportable. Unlike platelets and other cell-based therapy, PEVs do not get trapped in the lung after injection and can reach the nervous system by crossing the barrier between the blood and nervous system. These characteristics offer PEVs as a promising candidate for future translational clinical trials. Clinically, potential therapeutic benefits of PEVs in early-stage ALS patients may include the prevention of disease progression and an overall higher quality of life compared to those without intervention. In late-stage ALS patients, PEVs may potentially reverse neural degeneration, aid in the recovery of motor function, and renew life. Thus, we see little if any risk associated with the use of this drug in treating ALS patients. Time to Patient Benefit. This project will provide proof-of-concept data that will allow us to initiate human clinical trials in ALS patients soon. It is anticipated that the clinical trials will be supported by the ALS Foundation to assist in patient recruitment and considered for orphan designation in the U.S. and Europe with FDA approval for a clinical trial coming as early as 2027. Study Contributions to ALS and Other Degenerative Neurological Diseases. PEVs offer a new therapy that can repair the damaged blood-nervous system barrier and provide an innovative approach for treatment of ALS. The efficacy of PEVs in repairing damaged endothelial cells and improving neurological function in ALS animal model will lay the groundwork for clinical trials in ALS patients. As disruption of blood-nervous system barrier function is also observed in other conditions such as stroke, multiple sclerosis, brain injury, and Alzheimer’s diseases, these studies will also provide a blueprint for the use of PEVs for treatment of other neurodegenerati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310138
Entities
People
- Amit Srivastava
Organizations
- Thomas Jefferson University
- United States Army