Clinical Development of ISGylation Diagnostic Biomarker for ALS
Abstract
This grant aims to establish a new non-invasive biomarker for the quick diagnosis of amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), or both in veterans and civilians, as well as two distinct prototype assays (WesTM and sandwich ELISA) for measuring this biomarker in clinical settings. ALS is also known as Lou Gehrig s disease. It is a rare and incurable neurodegenerative disease caused by the slow deterioration and death of motor neurons, which are specialized cells in the brain and spinal cord that control the muscles throughout the body that mediate voluntary movements, including chewing, walking, and talking. Permanent motor neuron loss leads to paralysis and eventual death, generally from respiratory failure. There are two forms of ALS: sporadic ALS (approximately 90% of cases) and familial ALS (approximately 5%-10% of cases). In both forms, the symptoms are the same (consequences of motor neuron loss) and the average life expectancy is about 2 to 5 years from the time of diagnosis. Although ALS is rare in the general population, research supported by the U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) has revealed that military Veterans are at a nearly 60% greater risk of ALS than people with no history of military service. The causes of ALS are not fully understood in civilians or Veterans. However, TBI has been identified as a risk factor for ALS in Veterans. TBI due to traumatic incidents (e.g., falls, assaults, car accidents, etc.) is a major cause of death and disability among American civilians and Veterans. For both populations, ALS-like symptoms have been detected in those afflicted with TBIs. Although there is no cure for ALS, two U.S. Food and Drug Administration-approved medications, riluzole (Rilutek) and edaravone (Radicava), prolong life by a few months in some patients and, most importantly, slow disease progression best in patients who are in the early stages of disease. Hence, there is an urgent need to find diagnostic markers that can be used for the early diagnosis of ALS in Veterans and civilians unexposed/exposed to TBI to begin treatment earlier and slow the disease progression. Excitingly, my group has identified a potential diagnostic biomarker known as ISGylation -- a biological process wherein a small protein called ISG15 (Interferon-Stimulated Gene 15) is attached to various other proteins and alters their normal cellular functions -- that could help inform the diagnosis of ALS (without the previous history of TBI) and TBI- ALS (TBI-exposed Veterans who are later diagnosed with ALS) in Veterans. We have found that ISGylation is elevated in the spinal cords and brains of individuals with ALS and TBI-ALS. More recently, we found ISGylation circulating in the cerebrospinal fluid (CSF), a colorless body fluid that surrounds and protects the brain and spinal cord, and blood and urine samples of ALS patients. Together, these findings suggest that ISGylation is a promising potential liquid biopsy biomarker for the diagnosis of ALS and TBI-ALS Veterans and civilians. We do not know if ISGylation can detect a TBI exposure in non-ALS Veterans or civilians. In the current grant, we aim to explore the clinical utility of using ISGylation biomarker for ALS, TBI-ALS, and TBI conditions using liquid biopsies (CSF, blood and urine) archived in biorepositories and/or collected from living patients. Our ultimate goal is to develop and commercialize an ISGylation biomarker assessment tool to advance ALS patient care. We have already established a quantitative 3-hour automated test (WesTM assay) to measure ISGylation in liquid biopsies. In the current application, we propose to develop a 15-min specialized assay called a sandwich ELISA assay for measuring ISGylation in liquid-biopsies. For that, I have assembled an outstanding team of investigators with a track record of expertise in the clinical development of a rapid 15-min blood test usin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310257
Entities
People
- Shyamal Desai
Organizations
- LSU Health Sciences Center New Orleans
- United States Army