Pilot Trial of Baricitinib for ALS Patients and Asymptomatic Mutant C9ORF72 Carriers Including Novel Peripheral Immune Cell Profiling and CSF Biomarkers
Abstract
Objectives and Rationale of the Study: Amyotrophic lateral sclerosis (ALS) is a devastating neurologic illness with an average life expectancy of 2 to 3 years. While no disease-modifying therapies have been approved by the Food and Drug Administration (FDA), drug repurposing of FDA-approved drugs offers an expedited path by expanding the indication. Converging evidence reveals that inflammation in spinal cord is an important component of the pathology of ALS, but the causes of the inflammatory signaling remain elusive. Recently, the Albers lab discovered a root cause of inflammation is present in the central nervous system (CNS) of patients with the C9orf72 mutation, the most common genetic mutation in both familial and sporadic ALS cases. In animal models, activation of type I interferon signaling by cytoplasmic double stranded RNA (cdsRNA) leads to propagated neurodegeneration within a neural circuit. cdsRNA and type I interferon signaling is robustly active within the CNS of subsets of patients with ALS in autopsied brains. Further study of these brains identified a candidate biomarker of this specific trigger of inflammation, and profiles of cerebrospinal fluid (CSF) from living ALS patients also contained this inflammatory biomarker. It is a biosensor for dsRNA that increases with inflammation and is activated by binding dsRNA. Both the total levels and the activated levels can be quantified in the CSF of living patients. These markers are candidate predictive and prognostic biomarkers. In cultured human neurons, activation of type I interferon signaling results in neuronal death within 48 hours. Baricitinib, an FDA-approved drug for rheumatoid arthritis that blocks type I interferon signaling, also protects cultured human neurons from death in a dose-dependent manner. A related JAK inhibitor reversed the neuroinflammation and prevented neuronal death in the mouse model. This work has laid the foundation for the design of a mechanistic, biomarker-driven trial. We propose to ascertain whether baricitinib 2 mg per day and 4 mg per day reaches therapeutic levels in the CSF and whether it suppresses established inflammatory biomarkers and neuronal death biomarkers in the CSF and plasma. All participants recruited into this trial will have evidence of abnormal type I interferon signaling in their CSF at baseline. Types of Patients that will be Helped by the Study: Both symptomatic patients with ALS and asymptomatic patients with mutations in ALS-causing genes will be recruited into this trial. The knowledge gained from this trial has the potential to help through the discovery and validation of diagnostic, prognostic, and pharmacodynamic biomarkers and assess the ability of an FDA-approved drug to modulate these biomarkers in a therapeutic direction. Potential Clinical Applications and Benefits: The blood and spinal markers of inflammation identified within this study may serve as diagnostic, prognostic, and pharmacodynamic biomarkers for ALS. Contributions to Advance Patient Care, Treatment, Quality of Life, and Management of ALS: A successful trial will set the stage for larger clinical trials using these biomarkers and / or this FDA-approved drug to assist in the development of disease modifying therapies for ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210293
Entities
People
- Mark W Albers
Organizations
- Massachusetts General Hospital
- United States Army