BLRD Research Career Scientist Award Application

Portland Va Medical Center, Portland OR

Investigators

Linked publications & trials

Abstract

The mission of my Neuroimmunology Research Program is to develop a deep biological understanding of autoimmune, demyelinating and neurodegenerative processes that affect the central nervous system (CNS) and certain types of cancer and to identify and test novel disease-relevant therapies that can be brought to market to treat and/or cure these conditions. Veterans are currently developing intractable chronic neurological diseases such as multiple sclerosis (MS) and stroke, service related injuries including traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), substance abuse of methamphetamine and alcohol and cancer. Studies carried out by our laboratory are highly relevant to these devastating conditions due to our development of a novel therapy, DRhQ, that targets a common underlying mechanism, the MIF/CD74 axis that promotes chronic inflammation in the CNS and tumor growth in cancers. The result of MIF/CD74 signaling is peptide-specific T- effector cell activation and recruitment of inflammatory cells from blood into the CNS. Our main interest has been multiple sclerosis, a paralytic disease that affects ~1 million Americans. We recently discovered that MS males with high-expression MIF gene polymorphisms have an increased risk of developing progressive MS that results in severe loss of brain and motor functions (PNAS 2017). To date there are few if any treatments that can prevent conversion from relapsing to progressive MS. This unmet need stimulated our design of a third- generation VA and OHSU patent-protected CD74 ligand called DRhQ, now licensed by VA/OHSU to Artielle ImmunoTherapeutics Inc. DRhQ has increased affinity for CD74 and is thus a more potent inhibitor of MIF-1 and MIF-2 binding than our previous constructs. Moreover, DRhQ treatment of chronic EAE reversed demyelination in corpus collosum and optic nerves, making it an ideal candidate drug for blocking transition from relapsing to progressive MS. This discovery now supports a precision medicine approach for treatment of patients who are high MIF expressers. We currently are pursuing commercialization of DRhQ through Phase 1, 2 and 3 clinical trials. Our recent investigations identified key excipients to maintain >95% monomeric DRhQ as required by FDA for clinical testing. Our current strategy is to manufacture monomeric DRhQ suitable for human studies and carry out a first-in-human, FDA-approved Phase 1 study in healthy individuals to establish safety, tolerability and biomarker activities of the DRhQ drug substance (hopefully starting in 2025). Currently we are working with Virogenomics BioDevelopment, Inc. and the Gates Biomanufacturing Facility, Denver, CO for the manufacturing and purification steps. Assuming positive Phase 1 results, we then plan to carry out Phase 2 and Phase 3 trials using DRhQ to treat MS, stroke, TBI, methamphetamine use disorder and cancer in NIH and VA multicenter studies. These proposed clinical trials leading to commercialization of DRhQ could have a formidable impact on many human diseases, including those targeted by VA Research as essential for Veterans’ health.