Aicardi Goutires Syndrome (AGS) is a rare genetic disorder of excessive interferon (IFN) production, resulting in severe, systemic inflammatory injury and potentially profound disabilities. Most individuals affected by AGS exhibit some degree of neurologic impairment, ranging from mild spastic paraparesis to severe global developmental delay. Additionally, interferon overexpression results in systemic manifestations and recurrent aseptic fevers with severe, chronic irritability. AGS therapeutic trials are limited by heterogeneous patient populations and the lack of disease-specific outcome measures.
In Specific Aim 1, we will characterize clinically distinct AGS subgroups at the time of presentation and assess correlation with longitudinal history. We anticipate the identification of cohorts based on statistically relevant disease features that best predict clinical trajectory and outcome.
In Specific Aim 2, we will define a novel AGS rating scale to assess longitudinal change. We hypothesize that application of a disease-specific clinical rating scale at defined time points will more closely correlate with disease progression compared to a daily symptom diary and traditional clinical outcome assessment tool results obtained in Project 1.
In Specific Aim 3, we will explore the proportionality between a prospective biomarker, interferon signaling gene (ISG) expression, and clinical outcomes. The expected outcome of these aims is the development of tools for clinical trial readiness in AGS. We will identify clinically distinct subgroups of AGS, design an AGS-specific clinical rating scale, and explore the relationship of ISGs to clinical disease. It is expected that the development of these tools will facilitate clinical trial design, with immediate utilization in this setting.
Urgent need for clinical trial readiness has been demonstrated by a recent expanded access use pilot study using baricitinib, a JAK inhibitor (NCT01724580; JAGA) in which we demonstrated that current outcome assessment tools do not adequately capture the impact of the disease and the subsequent improvement. In this proposal, we will begin to bridge those gaps by identifying clinically distinct subgroups of AGS, designing an AGS-specific clinical rating scale, and exploring the relationship of a novel biomarker, interferon signaling genes, to clinical disease. It is expected that the development of these tools will facilitate clinical trial design, with immediate utilization in this setting.
