Composite Interferon Signaling Response Biomarker in Aicardi Goutières Syndrome

Aicardi-Goutières Syndrome (AGS) is a heritable interferonopathy that is now treatable by blocking the interferon receptor, IFNAR. However, AGS does not have any biomarkers to guide therapeutic decision-making. We propose to leverage our active clinical program in AGS, currently managing over 170 affected individuals, and our demonstrated ability to measure the Interferon Signaling Response (ISR) to explore a composite biomarker for this context of use. This work is enabled by a rigorous clinical data science environment in our NIH-funded consortium, the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), the support of the new Center for Diagnostic Innovation (CDI) at CHOP, and a multidisciplinary investigative team including disease experts, outcome validation teams, biomarker validation research staff, patient advocates, data analysts, and biostatisticians. This team will explore the ISR as a monitoring biomarker in the context of AGS therapies, which will transform our ability to treat this rare disease population. In Aim 1, we will transition this test to the CDI, defining its analytic and clinical validity for the Context of Use (COU). In Aim 2, we will test the use of the ISR and thresholds prospectively in its COU by using it to guide therapy modification in our active clinical AGS therapy program, which treats more than a dozen newly affected subjects a year. At the conclusion of this program, we expect to be able to submit the ISR to the FDA for consideration as part of the biomarker qualification program. The overall expected outcome of this proposal is the demonstration of the ISR as fit-for-purpose as a disease monitoring biomarker in AGS therapies and readiness to advance the ISR to full clinical biomarker validation. Project Number: 1R61NS146528-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Adeline Vanderver (+2 co-PIs) | Institution: CHILDREN'S HOSP OF PHILADELPHIA, PHILADELPHIA, PA | Award Amount: $775,490 | Activity Code: R61 | Study Section: Special Emphasis Panel[ZRG1 BN-H (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11290952