Inflammation in nerve tissue is a common feature seen in many mouse models of demyelinating forms of Charcot-Marie-Tooth disease, a long-standing observation from the team of Dr. Rudolph Martini at the University Hospital Würzburg. What is less clear is whether similar inflammatory processes occur in axonal forms of CMT, like CMT2J, and whether this inflammation contributes to nerve damage.

A key driver of this process is the macrophage, a type of immune cell that normally helps to maintain tissue health by clearing debris and supporting repair of damaged cells. However, in certain disease settings macrophage activation can be harmful and amplify inflammation resulting in worsened tissue damage. If this type of “bad” macrophage activity is a driver of CMT disease, then blocking it may offer a new therapeutic strategy.

This idea was the focus of Dr. Martini’s recently completed CMTRF-funded project. The work, conducted by Dr. Dennis Klein of the Martini lab, investigated a drug called PLX5622, which blocks the macrophage-related receptor of CSF1R. This receptor is critical to attract and activate macrophages at sites of inflammation within the body. By inhibiting CSF1R, PLX5622 may reduce macrophage activity in affected tissues.

To test this potential therapeutic approach for CMT2J, Drs. Martini and Klein used mice with a distinct genetic mutation (T124M) in the myelin protein zero (MPZ) gene.

Early results from this study were mixed. Young CMT2J mice with two copies of the T124M mutation developed a severe form of CMT2J, even more severe than most CMT2J patients, within six months of life. When these mice were treated with PLX5622, macrophage numbers in the nerve were successfully reduced. However, the animal’s physical abilities did not improve, and the nerve structure and nerve fibers appeared to worsen. It was concluded that PLX5622 is not a viable treatment for very severe cases of CMT2J.

Encouraging findings came from experiments involving mice with only one copy of the T124M mutation in MPZ. These mice developed a late-onset form of CMT that appeared by 18 months of age and more closely mimicked CMT2J in humans. Treatment of these animals with PLX5622 resulted in a significant reduction in nerve macrophages and substantially improved nerve structure and function.

Drs. Martini and Klein then evaluated a “pulse” treatment regiment, giving PLX5622 for three months, followed by a three-month break. This was designed to limit side effects of the drug, since macrophages elsewhere in the body perform beneficial roles. During the three-month break from treatment, macrophages returned to nerves, resulting in loss of some of the nerve structure. Correspondingly, the physical improvements gained during the three-month treatment window were also lost following drug withdrawal.

Overall, Dr. Martini’s findings highlight that inflammation and macrophage activity can influence the disease progression in CMT2J, a finding that likely extends to other axonal forms of CMT. The potential of disrupting macrophage activation as a treatment for axonal CMT holds promise; however, a more selective approach that blocks only the harmful macrophages at the nerve while sparing the helpful ones is likely necessary. Parts of the study were recently published in the journal Glia (http://doi.org/10.1002/glia.70074).