A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury

Abstract

Neurovascular, autoimmune, and traumatic injuries of the central nervous system (CNS) all have in common an initial acute inflammatory response mediated by influx across the blood-brain barrier of activated mononuclear cells followed by chronic and often progressive disability. Although some anti-inflammatory therapies can reduce cellular infiltration into the initial lesions, there are essentially no effective treatments for the progressive phase. We here review the successful treatment of animal models for four separate neuroinflammatory and neurodegenerative CNS conditions using a single partial MHC class II construct called DRa1-hMOG-35-55 or its newest iteration, DRa1(L50Q)-hMOG-35-55 (DRhQ) that can be administered without a need for class II tissue type matching due to the conserved DRα1 moiety of the drug. These constructs antagonize the cognate TCR and bind with high affinity to their cell-bound CD74 receptor on macrophages and dendritic cells, thereby competitively inhibiting downstream signaling and pro-inflammatory effects of macrophage migration inhibitory factor (MIF) and its homolog, d-dopachrome tautomerase (D-DT=MIF-2) that bind to identical residues of CD74 leading to progressive disease. These effects suggest the existence of a common pathogenic mechanism involving a chemokine-driven influx of activated monocytes into the CNS tissue that can be reversed by parenteral injection of the DRa1-MOG-35-55 constructs that also induce anti-inflammatory macrophages and microglia within the CNS. Due to their ability to block this common pathway, these novel drugs appear to be prime candidates for therapy of a wide range of neuroinflammatory and neurodegenerative CNS conditions.

Adult astrocytes from reptiles are resistant to proinflammatory activation via sustaining Vav1 expression

“…As a potent proinflammatory cytokine, MIF is abundantly expressed in the pathological CNS of mammals and associated with clinical worsening of multiple sclerosis (MS), Alzheimer's disease (AD), and traumatic spinal cord ( 10 , 30 , 45 , 46 ). Astrocytes, together with microglia, are certainly the primary target cells of MIF and the active players that contribute to the inflammatory pathology ( 10 , 47 ). In the present study, gAS have been shown to be insensitive to the proinflammatory stimuli of gMIF, suggesting a unique inflammation-suppressive function of the immature adult astrocytes.…”

Major histocompatibility complex Class II-based therapy for stroke

“…[ 10 ] Partial major histocompatibility complex (MHC) Class II constructs can limit early immune response, therefore, sequestering ischemic-induced inflammation. [ 11 12 ] MHC Class II constructs are a viable stroke treatment because of their neuroantigen-specific modulation of T-cells as well as CD74 signaling. [ 11 12 15 ]…”

“…[ 11 12 ] MHC Class II constructs are a viable stroke treatment because of their neuroantigen-specific modulation of T-cells as well as CD74 signaling. [ 11 12 15 ]…”

“…MHC Class II constructs can potentially mitigate cell death in traumatic brain injury (TBI) and stroke. [ 12 ] DRhQ and DRmQ represent advanced MHC Class II constructs that have shown safety and efficacy in preclinical models of TBI and stroke. DRhQ was created for clinical development while DRmQ was designed as a preclinical therapeutic for demonstrating proof-of-concept efficacy in animal models of autoimmune encephalomyelitis.…”

Surviving the storm: Dealing with COVID-19

“…Thus, the simpler DRhQ construct was designed, retaining just the conserved-in-human DRα1 domain (without the polymorphic HLA-DRβ1 domain) linked to the MOG-35-55 peptide extension, with the added benefit that it can be administered to all recipients without need for tissue type matching. This has enabled use of the DRα1-MOG-35-55 construct to reverse ongoing neuroinflammation and disease signs in animal models of multiple sclerosis, stroke, methamphetamine disorders and traumatic brain injury [8]. These and other studies ( [9][10][11] & unpublished data) revealed down-regulation of multiple proinflammatory components driven by both innate and adaptive immune responses that also contribute to the SARS-CoV-2 cytokine storm, including complement receptor C5aR1, platelet activation, IL-1β, IL-2, IL-6, TNF-α, CCR2 (receptor for CCL2) and CXCR2.…”