Preclinical and neuroimmunologic study of RTL1000 for methamphetamine addiction

DESCRIPTION provided by applicant Methamphetamine MA dependence is associated with long term damage to regions of the brain that control cognitive and psychiatric function One third to one half of MA dependent adults experience persistent cognitive and other psychiatric disorders up to three years or longer into remission The neuropsychiatric impairments that persist following abstinence are associated with poorer treatment outcomes increased relapse and lower treatment retention rates Emerging evidence demonstrates how immune factors can influence addictive behaviors and contribute to relapse Our lead compound recombinant T cell receptor ligand RTL a partial major histocompatibility complex pMHC class II construct with a tethered myelin peptide pDR hMOG addresses the long term neuroimmune effects of MA addiction and offers a new strategy to treat the persistent MA induced neuronal damage and neuropsychiatric impairments which contribute to relapse RTLs bind to and downregulate expression of the invariant chain CD the primary receptor for macrophage migration inhibitory factor and a key inflammatory mediator in a number of diseases including alcoholism and MA dependence The proposed application builds on our previous research by using complimentary human rodent and cross species experiments that will allow us to rapidly move RTL along the drug development pipeline toward readiness for clinical translation The primary objective of this Phase I STTR project is to evaluate RTL as a medication for MA dependence and test whether RTL can promote abstinent like behavior and reduce relapse using two different animal models Secondary objectives will i characterize the effects of RTL immunotherapy on the CD NF B inflammatory signaling cascade and ii determine CD expression and response to RTL in monocytes from adults with and without a history of MA dependence Collectively these secondary objective will i establish the degree to which specific inflammatory signals contribute to MA intake and relapse behaviors and ii determine the feasibility of using CD as a future biomarker for assessing RTL immunotherapy treatment response in patients with MA dependence We expect that following the completion of this one year project we will have substantial evidence to support a new treatment strategy for MA addiction a strategy which addresses problems that are central to the underlying pathophysiology of MA addiction PUBLIC HEALTH RELEVANCE Discovery of an immunotherapy i e RTL that could improve brain repair and neuropsychiatric recovery following methamphetamine MA addiction would represent a major scientific breakthrough that could broadly impact addiction treatment This translational research project will evaluate RTL as a medication for MA dependence and test whether or not RTL can promote abstinent like behavior and reduce relapse in addition to its cognitive enhancing and anti inflammatory effects Secondary objectives are to i evaluate the degree to which inflammatory immune responses contribute to MA relapse behaviors and ii determine the feasibility of using CD as a future biomarker for assessing RTL immunotherapy treatment response in patients with MA dependence A major outcome of the proposed project will be to establish the preclinical efficacy of RTL immunotherapy for the treatment of MA dependence with the goal of rapidly moving RTL immunotherapy closer to readiness for human clinical trials as a medication to reduce relapse