Arthur Vandenbark and team find treatment dose for MS is sex dependent

High dose of DRα1-mMOG-35-55 reduces demyelination and leukocyte infiltration in female mice with chronic EAE.
High dose of DRα1-mMOG-35-55 reduces demyelination and leukocyte infiltration in female mice with chronic EAE.

One of the main challenges in treating multiple sclerosis is reversing the effects of accumulated damage to the central nervous system. Damage to myelin, which coats and protects axons, and chronic axonal loss due to the absence of myelin are hallmarks of the disease. Most of the available drugs for MS are anti-inflammatory and used to treat the most common type of MS: relapsing-remitting. It is not clear to what extent these drugs help repair damaged axons and create new myelin sheaths. Repairing or stopping chronic myelin damage may reduce or halt MS progression.

A team led by Arthur A. Vandenbark, Ph.D., used a mouse model of MS to evaluate potencies of a genetic therapy, called pMHC class II constructs, on the progressive form of this MS model. Vandenbark, professor in the OHSU Multiple Sclerosis Center, and his team have previously shown that these pMHC class II constructs may prevent or reverse clinical signs of neuro-inflammatory diseases, including the mouse model of MS.

The research, published May 6 in the Journal of Neuroinflammation, demonstrated that treating the mouse model of chronic MS with these constructs significantly reversed the clinical severity of the disease. The treatment also reduced continued loss of myelin and the associated axonal damage in the central nervous system.

The findings demonstrated that the effective dose of pMHC constructs was sex dependent and might be regulated by estrogen signaling through estrogen receptor alpha, a nuclear receptor that is activated by the sex hormone estrogen. The team identified the importance of the dose of these constructs, particularly when used in future therapies for women with progressive MS. Of the 400,000 people in the United States with MS, most are women.

This work may potentially support the design of future clinical trials using pMHC for treatment of progressive MS.

In addition to Vandenbark and first authors Gil Benedek and Priya Chaudhary, co-authors include Roberto Meza-Romero, Evan Calkins, Gail Kent, Halina Offner, and Dennis Bourdette.

This work was supported by NIH grants AI 122574 (to AAV) and the Merit Award BX000226 (to AAV) through the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development.