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Macrophages Expressing a Modified Human Sodium Channel Protein Prevent or Reverse Multiple Sclerosis in a Mouse Model

By BiotechDaily International staff writers
Posted on 14 Jun 2013
Genetically engineered mouse macrophages expressing the human gene (SCN5A) that encodes the NaVI.5 (sodium channel, voltage-gated, type V, alpha subunit) sodium channel protein were used to demonstrate the potential use of these modified immune cells for the treatment of muscular sclerosis (MS).

NaVI.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram.

Investigators at the University of Wisconsin (Madison, USA) had shown previously that a splice variant of NaV1.5 was expressed intracellularly in human – but not mouse - macrophages, and that it regulated cellular signaling. The lack of this channel protein in mouse macrophages made it very difficult to study.

To counter this problem the investigators developed a novel transgenic mouse model (C57BL6c-fms-hSCN5A), in which the human macrophage NaV1.5 splice variant was expressed in vivo in mouse macrophages. They used these modified macrophages in studies carried out on mice with experimental autoimmune encephalomyelitis—a syndrome that closely mimics human muscular sclerosis.

Results published in the June 2013 issue of the Journal of Neuropathology and Experimental Neurology revealed that the mice expressing human NaV1.5 were protected from experimental autoimmune encephalomyelitis. The modified macrophages sought out the lesions caused by the disease and promoted recovery.

Mice with experimental autoimmune encephalomyelitis that lacked human NaV1.5 macrophages displayed symptoms of a chronic disease, which progressed from weakness of the back and front limbs to complete paralysis of the hind limbs. When macrophages expressing human NaV1.5 were transplanted into these mice, the animals regained the ability to walk. Mice treated with a placebo solution or normal mouse macrophages did not show any signs of recovery or became progressively more ill.

"This finding was unexpected because we were not sure how much damage they would do, versus how much cleaning up they would do,'' said senior author Dr. Michael Carrithers, assistant professor of neurology at the University of Wisconsin. "Some people thought the mice would get more ill, but we found that it protected them and they either had no disease or a very mild case."

The question remains as to why human NaV1.5 macrophages fail to protect humans from MS. "Why are these repair mechanisms deficient in patients with MS and what can we do to enhance them?'' asked Dr. Carrithers. "The long-range goal is to develop the NaV1.5 enhanced macrophages as a treatment for people with MS."


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