Inner and Outer Nuclear Layer Atrophy of the Retina as Novel and Distinguishing Biomarkers for Defining and Tracking Progressive Multiple Sclerosis
Abstract
Background: The current proposal addresses the FY18 MSRP Investigator-Initiated Research Award Focus Area Correlates of Disease Activity and Progression in MS. The proposal directly addresses this focus area through its primary objective of confirming and validating that changes in the thickness of particular layers within the retina (the inner and outer nuclear layers) of people with multiple sclerosis (MS) correlate with disease progression, specifically in progressive MS(PMS). This is an important undertaking since there is currently a desperate need for high-quality, sensitive measures of degeneration of nervous tissue (the principal substrate underlying disability in MS) within the central nervous system that are specific to PMS. Unlike the relapsing-remitting form of MS for which there is an abundance of clinical, imaging, and other biomarkers that can be successfully applied, both in clinical practice as well as clinical trials including early phase clinical trials, there is a lack of biomarkers or outcomes that are specific to PMS. Indeed, this major unmet need in PMS has contributed significantly towards hindering advances in PMS in general, the testing of potential therapeutics in PMS, and overall lack of successful development of drugs for PMS. In part, this may be because a greater degree of disease biology in PMS relates to degeneration of nervous tissue that is not directly due to ongoing or current inflammation. Our proposal helps to address these gaps in PMS and meet a key unmet need in PMS. PMS is a form of MS characterized by steady and gradual accumulation of disability, of which there are two principal subtypes, primary and secondary PMS. Currently, there is only a single U.S. Food & Drug Administration-approved treatment for the primary PMS subtype of this form of MS, the benefit of which is modest at best. Based on our strong preliminary data using optical coherence tomography (OCT), which is the optical analogue of ultrasound imaging, and allows rapid, inexpensive, reliable, reproducible, and high-resolution quantification of the individual layers of the retina, we have identified a pattern of retinal thinning that appears to be specific for PMS. This finding, which could represent a significant milestone toward advancing the monitoring, research, and care of PMS, requires verification, which indeed represents the primary aim of this project. A secondary objective of this study proposal is to assess the impact of ibudilast, a therapy that potentially helps to protect the central nervous system, on the retinal measures that we have found to be specific for PMS. In alignment with the program announcement, the proposed research project will utilize pre-existing OCT and other imaging and clinical data acquired from well-characterized, adequately controlled, and sufficiently powered patient cohorts who were studied as part of the completed SPRINT-MS trial (96-week, placebo-controlled study of the ibudilast in 255 combined primary and secondary PMS patients). Study participants underwent clinical and imaging (including OCT) assessments every 24 weeks. The study found that relative to placebo, ibudilast reduced rates of whole brain volume reduction in PMS by 48% and may indeed protect the central nervous system, highlighting the SPRINT-MS study cohort as opportune to meet the objectives of the current research proposal. Objective 1: To confirm and validate that people with PMS exhibit a pattern of retinal thinning that is different from people with relapsing-remitting MS, and is therefore of specific use in PMS, fulfilling an important need in the field of PMS. Hypothesis/Expected outcomes 1: Based on our strong preliminary data we hypothesize that PMS patients exhibit a specific pattern of retinal thinning that more closely mirrors the accumulation of disability in PMS than changes on magnetic resonance imaging (MRI) of the head. Objective 2: To confirm that ibudilast is indeed neuroprotective in P
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910631
Entities
People
- Shiv Saidha
Organizations
- Johns Hopkins University
- United States Army