Treatment of CNS damage from non-disordered drug use with DRhQ, a novel regulator of CD74 signaling

About This Grant

PROJECT ABSTRACT Non-disordered drug use (NDDU) is a severe public health concern. Stimulants like methamphetamine cause long-term damage to regions of the brain that regulate cognitive functions, psychiatric symptoms, and promote drug-seeking behavior. Methamphetamine use increases the risk of stroke and damage to white matter (WM), both of which can impact cognitive function. We have a collection of MHC class II constructs that bind to and downregulate the expression of CD74—the primary receptor for macrophage migration inhibitory factor (MIF), a key inflammatory indicator of methamphetamine use. These constructs have a therapeutic impact in animal models of stroke and can reverse the axonal dysfunction observed in a mouse model of multiple sclerosis. These constructs also have been shown to improve cognitive function and decrease the inflammation associated with exposure to methamphetamine, suggesting a highly effective therapeutic profile. Methamphetamine has been shown to exacerbate the increased infarct volume and decreased cognitive function observed following transient middle cerebral artery occlusion in mice. The direct effects of methamphetamine use on white matter function and vulnerability to ischemia remain unexplored. The primary objective of this STTR proposal is to evaluate our third-generation molecule, DRhQ, which has been optimized for CD74 binding and future clinical use, by determining whether it can reduce or even reverse neuronal and axonal damage caused by methamphetamine use. In Aim 1, we will evaluate whether DRhQ decreases infarct volume and improves cognitive function from methamphetamine-associated stroke. In Aim 2, we will examine the impact of methamphetamine alone on the function of myelinated and unmyelinated axons in the corpus callosum from mice, and then, we will determine whether any reduction in axon function and integrity can be reversed following treatment with DRhQ. At the end of this Phase 1 feasibility study, we will have determined whether DRhQ has the potential to be an effective treatment for neuronal and axonal damage caused by methamphetamine use including whether it can reduce or reverse the severity observed in methamphetamine-associated stroke. If successful, DRhQ may be a valuable therapeutic in treating complications from methamphetamine use. Phase 2 studies would look to expand preclinical testing and work to advance DRhQ into clinical testing.