In vivo tracking of innate immune activation and therapeutic response in MS mouse models using [18F]OP-801

Stanford University, Stanford CA

Investigators

Abstract

Summary: Multiple sclerosis (MS), a chronic, demyelinating, neuroinflammatory disease typically affecting young adults, often results in neurological deficits as disease progresses. Although multiple disease-modifying immunomodulatory therapies are available for MS, disease manifestations and treatment response are highly variable and difficult to predict in patients. Current standard of care imaging techniques used to diagnose and monitor MS unfortunately cannot provide early and specific molecular information regarding an individual’s immune signature in the central nervous system (CNS), thus limiting our ability to select the most appropriate therapy and obtain early predictors of response for any given patient. As such, there is a need for non-invasive molecular imaging strategies that provide real-time information about specific immune cells and their functional phenotypes in MS patients. Activated macrophages and microglia are the predominant immune cells associated with acute and chronic-active CNS lesions, suggesting that the combined presence, extent, location, and temporal dynamics of reactive macrophages/microglia have the potential to serve as clinically meaningful biomarkers of active MS. Unfortunately, existing imaging strategies for detecting activated macrophages and microglia lack specificity and cannot distinguish between beneficial (anti-inflammatory) and toxic (pro- inflammatory) immune responses. To address this limitation, we recently developed a novel 4th generation hydroxyl dendrimer PET radiotracer, [18F]OP-801, that is known to be selectively taken up (>95%) by reactive microglia and macrophages. This radiotracer, recently approved for clinical use, has shown tremendous promise in a murine model of sepsis, and we have generated encouraging preliminary data in a mouse model of chronic MS. Here, we propose to utilize [18F]OP-801 in two mouse models of MS (chronic and relapsing-remitting) across multiple disease stages, to assess the relationship with disease severity and central/peripheral inflammation, as well as monitoring responses to an FDA-approved immunomodulatory therapeutic. We hypothesize that [18F]OP- 801 can be used to detect and quantify in vivo macrophage- and microglia-driven immune responses in rodent models of MS, and that [18F]OP-801-PET can accurately predict disease progression and response to therapies. We will test our hypothesis with the following specific aims: 1) Characterize the relationship between [18F]OP- 801-PET signal, disease severity, and markers of central and peripheral inflammation in two mouse models of MS, and 2) Assess the ability of [18F]OP-801-PET versus TSPO-PET to predict and monitor responses to an FDA-approved immunomodulatory therapeutic. We therefore aim to establish the sensitivity and potential utility of [18F]OP-801 prior to use in MS patients. This research promises to provide critical in vivo information about the role and time course of macrophage- and microglia-driven immune responses in EAE and MS. Our proposed strategy using [18F]OP-801-PET could have far-reaching and significant impact as a clinically useful molecular imaging technique for mapping harmful innate immune activation in a range of neurological diseases.