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Horea Rus with a lab assistant in the laboratory

Horea Rus, MD, PhD, left, in his lab.

My lab discovered Response Gene to Complement (RGC)-32 as a gene involved in cell cycle activation and induced by complement activation.

We have cloned the mouse, rat and human RGC-32 gene and created the first RGC-32 knockout (KO) and conditional RGC-32 KO mouse.

We showed for the first time that this gene plays an important role in regulation of cell cycle in human endothelial cells, smooth muscle cells and cancer cells.

We also showed that RGC-32 is inducing epigenetic changes in colon cancer.

Our expertise in the RGC-32 biology and pathology positions our lab as a leader in this field. 

RGC-32 in pathogenesis of Multiple Sclerosis

Multiple sclerosis (MS) is a T-cell mediated autoimmune disease in which the immune system repeatedly attacks the myelin in the brain and spinal cord and continues to be a major concern in patient care- especially in young adults. Using an experimental mouse model of MS called experimental allergic encephalomyelitis (EAE), we investigated the role of the RGC-32 in mediating central nervous system (CNS) tissue damage.

It is known that RGC-32 is a downstream mediator of transforming growth factor beta (TGF-β) signaling pathways; and since TGF-β induces T helper 17 (Th17) cells differentiation and is mediating as well as astrocytes profibrotic effects, we examined the role of RGC-32 in inducing Th17 cells in vitro and in vivo using EAE.

Using this approach, we have identified an impaired in vitro Th17 cells differentiation in the absence of RGC-32. We further investigated the Th17 cells differentiation in vivo during EAE and we found that RGC-32 KO mice have also an impaired Th17 differentiation. In addition, we found that RGC-32 KO mice display an attenuated EAE phenotype accompanied by decreased CNS inflammation, demyelination and astrocyte phenotypic changes.

RGC-32 as a biomarker of disease activity and response to treatment in multiple sclerosis

We have identified three potentially useful blood-based biomarkers of relapse and of the response to glatiramer acetate treatment in patients with relapsing-remitting multiple sclerosis (RRMS). 

The study had its roots in our prior findings that the RGC–32 is expressed by CD3+ and CD4+ T cells in peripheral blood mononuclear cells (PBMCs) and in brain tissue from MS patients. In addition, RGC-32 regulates the expressions of Fas ligand (FasL) and interleukin-21 (IL-21), and the activities of CDC2 and Akt. 

We explored the potential value of RGC-32, FasL, IL-21, CDC2, and Akt as longitudinal biomarkers of relapse and as a way of gauging the response to the treatment of RRMS patients with glatiramer acetate – one of the most common immunomodulatory approaches used in RRMS therapy. 

Acute relapse was associated with decreased expression of RGC-32 and FasL (both P less than .0001) and increased expression of IL-21 (P = .04). No relapse-associated changes in CDC2 or Akt were evident. Compared with those who did not respond to glatiramer acetate, responders displayed an increased expression of RGC-32 and FasL (both p< .0001), and a decreased expression of IL-21 (P = .02).

Receiver operating characteristic analysis was done to find the cutoff values that best distinguished treatment responders from non-responders for each candidate biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to glatiramer acetate was 85%, 90%, and 85% in the same respective order. Further work needs to expand these results with RCG-32, FasL, and IL-21 to a randomized, controlled trial with the goal of tailoring treatment at the early stage of MS.

These novel findings indicate the potential importance of RGC-32 as a therapeutic target in multiple sclerosis, atherosclerosis and cancer. 

A patent was awarded on May 7, 2019 encompassing the work on biomarkers in Multiple Sclerosis. 

Patent Title: “Biomarkers for Predicting Relapse in Multiple Sclerosis”; Authors: Horea Rus, Cosmin Tegla.