Early, Intermediate, and Late Retinal Biomarkers for Assessing Neuroprotection Following Acute Optic Neuritis: Insight and Exploration of RENEW, Opicinumab in AON Phase 2 Clinical Trial
Abstract
Acute optic neuritis (AON, or inflammation of the optic nerve, the nerve that transmits visual signals from the retina of the eye to the brain), causes impairment of vision and typically results in injury to the insulation sheaths (myelin) surrounding the fibers or cables comprising the nerves. The fibers or cables of the optic nerves originate from the top layer of the retina (retinal nerve fiber layer; RNFL), and the cell bodies or nerve cells (ganglion cells) from which these fibers are derived are located in a layer under the RNFL called the ganglion cell layer (GCL). AON is a frequent manifestation of multiple sclerosis (MS), that also commonly occurs during the course of MS. Because the eye is the most external part of the central nervous system, it is amenable to structural and functional interrogation in ways that other parts of the brain cannot be investigated. For example, we now have highly sophisticated retinal imaging techniques (like optical coherence tomography; OCT – explained below) that allow us to image the retina with up to 20 times the resolution of standard MRI, and accurately quantify layers like the RNFL and GCL. Similarly, using physiology-based techniques like visual evoked potentials, the speed at which signals move from the eyes to the back of the brain can be measured. This provides information regarding the integrity of myelin, as a function of fiber insulation. In addition, we can clinically test the visual system by assessing ability to read letters at different levels of illumination/contrast. Because of the ability to test structure and function of the retina so easily and accurately, AON is now frequently used as an event of interest in the design of clinical trials of new medications that may act to protect nerves from injury (neuroprotection), or even promote new myelin to be put down (remyelination). The identification and development of therapies for neuroprotection and remyelination represent a key focus in MS research. However, clinical trials of such agents have been hampered because of a lack of validated techniques for testing their effectiveness, highlighting again the role of the visual system, and interest in studying AON for the testing of such drugs. The RENEW trial was a 32-week placebo-controlled study of opicinumab in AON. This drug to thought to turn on myelin producing cells and has been shown to have remyelinating and neuroprotective effects in animal models of MS, and has the potential to encourage remyelination and/or neuroprotection after attacks or relapses in MS (such as AON). In the current proposal we will re-analyze the entirety of the retinal OCT scans acquired in the RENEW trial. OCT, the optical analogue of ultrasound, allows extremely high-resolution retinal imaging and quantification of the integrity of the discrete retinal layers affected by AON. We will apply state-of-the-art validated techniques, including the highest level of quality control of the OCT images, and what is widely regarded as the best OCT image processing procedures to ensure the scans provide the most accurate quantification of the retinal layers of interest. In doing so, we will address the FY22 MSRP Investigator-Initiated Research Award Focus Area on Correlates of Disease Activity and Progression in MS, by validating the role of OCT in trials of potentially neuroprotective and/or remyelinating therapies, as well as providing novel insights regarding mechanisms of tissue injury following inflammatory attacks in AON and MS in general. Although the RENEW trial was deemed negative on account of not meeting the pre-specified primary outcome at a particular timepoint, based on our assessment, numerous relevant and important signals in the trial are actually highly suggestive of a treatment effect of opicinumab. We hypothesize that opicinumab treatment in AON was associated with significantly reduced amounts of GCL thinning (an early marker of nerve injury in the retina aft
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310551
Entities
People
- Shiv Saidha
Organizations
- Johns Hopkins University
- United States Army