"Loftis et al. explored a compelling hypothesis – that behavior changes in methamphetamine abuse may be the result of neuroinflammation. They used a partial MHC/neuroantigen peptide construct, one of a class of immunomodulatory recombinant T-cell receptor ligands (RTL) developed at OHSU, to show that cognitive effects of methamphetamine could be mitigated in mouse models. This is an important paper for several reasons: it's a unique therapeutic application of immune modulation (methamphetamine abuse), it is eminently translatable to humans, and it is one outcome of years of excellent work by OHSU immunologists that produced novel drugs with commercial potential for several important clinical problems. The manuscript reflects a well-conceived progression of basic discovery to the near bedside."
- Eric Orwoll, M.D.
Associate Dean for Clinical Science
This month's featured paper is titled, "Partial MHC/Neuroantigen Peptide Constructs: A Potential Neuroimmune-Based Treatment for Methamphetamine Addiction," and was published in PLoS One.
The co-principle investigators are: Jennifer Loftis, Ph.D., a Research Scientist at the Portland Veterans Affairs Medical Center and an Associate Professor in the Department of Psychiatry, and Marilyn Huckans, Ph.D., a Neuropsychologist at the Portland Veterans Affairs Medical Centerand an Associate Professor in the Department of Psychiatry.
Clare Wilhelm, Ph.D., a Research Scientist at the Portland Veterans Affairs Medical Center and an Assistant Professor in the Department of Psychiatry, and Arthur A. Vandenbark, Ph.D., a Senior Research Career Scientist at the Portland Veterans Affairs Medical Center and Professor in the Department of Molecular Microbiology & Immunology also contributed to this study.
April 23, 2013
Methamphetamine dependence is associated with long-term damage to regions of the brain that control cognitive and psychiatric function. A third to half or more of methamphetamine dependent adults experience persistent cognitive, mood, and other neuropsychiatric disorders up to three years or longer into remission. Importantly, the neuropsychiatric impairments that persist following abstinence are associated with poorer treatment outcomes — increased relapse rates, lower treatment retention rates, and reduced daily functioning.
To date, there are no Food and Drug Administration approved pharmacotherapies for methamphetamine addiction. Medication development for substance abuse, including methamphetamine, has historically been focused on targeting neurotransmitter systems with limited success. "One key drawback of neurotransmitter agonist or antagonist based therapies is that alone they do not offer a mechanism for repairing stimulant-induced neuronal injury," said Dr. Loftis. "This might be vital for successful recovery."
A growing literature shows that, in addition to neurotransmitter systems, methamphetamine also alters peripheral and central immune functions and that key immune factors likely play a role in the development of methamphetamine induced brain injury. "Collectively, these lines of evidence
The team's lead compound, recombinant T-cell receptor ligand (RTL) * instead addresses the long-term neuroimmune effects of methamphetamine addiction and offers a new strategy for the treatment of persistent methamphetamine induced central nervous system (CNS) injury and neuropsychiatric impairments.
A previous study in the Arthur Vandenbark Lab showed that treatment with pMHC class II constructs (a.k.a. RTL551) linked to antigenic peptides inhibits recruitment of inflammatory cells to the brain. As well, partial MHC constructs bind to and downregulate expression of CD74 — the primary receptor for macrophage migration inhibitory factor (MIF), a key inflammatory mediator in a number of diseases, including alcoholism. Because it was previously shown that a pMHC/neuroantigen peptide construct (RTL551) effectively reduces the inflammatory and behavioral effects of experimental models of multiple sclerosis and stroke, the scientists hypothesized that pMHC constructs could also effectively address the neuropsychiatric effects of chronic methamphetamine addiction.
In their pre-clinical study, the investigators found that mouse pMHC coupled to myelin peptide (RTL551) improves the learning and memory impairments and CNS inflammation induced by repeated methamphetamine exposure in two mouse models of methamphetamine addiction.
"We initially evaluated the efficacy of RTL551 when administered during continued methamphetamine exposure," said Dr. Huckans. "We found that humans frequently relapse during addiction treatment, so it is important to understand how treatments impact outcomes in a model of relapse and active use."
The team subsequently evaluated the efficacy of RTL551 administered during remission from repeated binge methamphetamine exposure; this treatment regimen closely models an optimal intervention strategy in humans where the goal is to treat persistent neuropsychiatric symptoms during remission from methamphetamine dependence.
"In all experiments, RTL551 successfully attenuated methamphetamine induced memory impairments in mice," said Dr. Huckans. "Moreover, mice tolerated both methamphetamine exposure models and RTL551 treatment without apparent difficulty." These initial results indicate that neuroimmune therapies, such as RTL551, may have potential as treatments for methamphetamine dependence and other substances of abuse.
RTL1000 ("humanized" RTL551) has extensive pre-clinical safety data and has progressed to Phase II clinical testing in multiple sclerosis patients. Thus, Drs. Loftis and Huckans said the team's next steps are to evaluate the safety and efficacy of RTL1000 as a treatment for methamphetamine addiction. Toward these objectives, the investigators are: 1) seeking final FDA approval to conduct a double-blind, placebo-controlled Phase I/II clinical trial, 2) strengthening their relationships with private sector investors and commercialization partners, 3) manufacturing RTL1000 to enable clinical studies, and 4) applying for federal grant support to help fund the clinical trial.
"If found to be safe and efficacious through subsequent Phase II and III clinical trials, RTL1000 hopefully will be approved to treat individuals entering early remission from methamphetamine addiction," said Dr. Huckans.
By helping methamphetamine addicted adults to quickly regain lost function and feel better following attempted abstinence, Dr. Loftis, said "RTL1000 may also help these individuals be less prone to relapse and better able to succeed in their daily lives. It could improve their quality of life."
*a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide (a.k.a. pDR2/MOG-35-55)
Pictured above: (From left) Arthur Vandenbark, Ph.D.; Clare Wilhelm, Ph.D.; Jennifer Loftis, Ph.D.; and Marilyn Huckans, Ph.D.
The Department of Veterans Affairs (VA) and Oregon Health & Science University (OHSU) own the RTL technology used in the RTL research that is discussed in part of this presentation. One investigator on the RTL studies has stock options in Virogenomics/Artielle, a company that has licensed the technology and may have interest in the results of the study. The VA and OHSU, and Drs. Loftis, Huckans and Vandenbark have rights to royalties from the licensing agreement with Artielle. These potential conflicts of interest have been reviewed and managed by the Conflict of Interest Committees at the Portland VA Medical Center and OHSU.
About the Paper of the Month
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, Ph.D., and Associate Dean for Clinical Science Eric Orwoll, M.D.
More Published Papers
The entire list of OHSU papers published this month is here.