IFB-088 Aids Myelin Formation in CMT1 Mouse Models
IFB-088, a small molecule that modulates a cell’s response to stress, improved myelin formation in mouse models of Charcot-Marie-Tooth type 1 (CMT1) disease, and this translated into faster nerve signal transmission and better motor function, a study found.
If the findings hold true in humans, they could lead to a potential new therapy for CMT1, the researchers noted.
The study, “Treatment with IFB-088 improves neuropathy in CMT1A and CMT1B mice,” was published in Molecular Neurobiology by an international team of researchers.
Certain genetic mutations cause damage to myelin, the fatty sheath that covers nerves and allows electrical signals to travel from the brain to the muscles, and back. Loss of myelin results in slower transmission of nerve signals, and this causes muscles to become weak and tired.
The most common form of CMT1, called subtype A (CMT1A), is caused by an extra copy of PMP22, a gene that codes the instructions for making a component of myelin. The second most common form, subtype B (CMT1B), is caused by mutations in MPZ, a gene that codes for myelin protein zero, another of its key components.
Studies have shown that the mutated version of these proteins builds up in the endoplasmic reticulum, a structure inside cells where proteins are produced, causing it to be stressed.
To suppress this, cells turn on an unfolded protein response (UPR), which reduces the amount of misshapen proteins. However, cells are not always able to properly cope with too much stress.
By keeping the UPR turned on, IFB-088 (icerguastat, also known as sephin1) is expected to give cells additional time to repair or dispose of misshapen proteins. In a mouse model of CMT1B, oral treatment with IFB-088 prevented motor symptoms, indicating that it could be effective in diseases caused by accumulating misfolded proteins.
Work by other scientists has shown that IFB-088 is also a potential therapy for amyotrophic lateral sclerosis and multiple sclerosis, two other neurodegenerative diseases. A Phase 1 clinical trial in healthy volunteers showed IFB-088 was safe and well tolerated with no serious side effects reported.
The researchers investigated the effects of IFB-088 in two mouse models of CMT1: C3-PMP22, a mouse model of CMT1A, and MpzR98C/+, a mouse model of CMT1B.
They first isolated spinal nerves from both MpzR98C/+ mice and healthy (wild-type) mice. Next, they grew them in the lab together with Schwann cells, a type of cell that makes myelin in the peripheral nervous system (outside the brain and spinal cord). The MpzR98C/+ spinal nerves had less myelin coverage than the wild-type ones. When the researchers added IFB-088 to the MpzR98C/+ spinal nerves, myelin coverage increased, however.
Some mice were treated with IFB-088, given by mouth directly into the esophagus twice a day. The remaining mice were given a placebo (saline) solution. As controls, the researchers also used wild-type mice.
The researchers watched for changes in the ability of mice to hold on to a grid and run on a rotating rod (rotarod) or on a treadmill. These abilities were lost in both MpzR98C/+ and C3-PMP22 mice compared with the wild-type mice. However, five-month treatment with IFB-088 made the animals able to run longer and increased their grip strength, indicating better motor function. Significantly greater grip strength was seen in C3-PMP22 males, but not females.
A nerve conduction velocity test revealed that electrical signals traveled faster through the nerves of IFB-088-treated mice than through those of saline-treated animals. This was true for both motor nerves (those that control the muscles) and sensory nerves (those that send signals to the brain).
Moreover, compared to the saline solution, treatment with IFB-088 decreased the g-ratio, a ratio of the inner versus outer diameter of a myelinated nerve fiber. A lower g-ratio means that the myelin sheath is thicker, and this may mean faster electrical signals.
“Our results demonstrate the capability of IFB-088 to treat a second mouse model of CMT1B and a mouse model of CMT1A, the most common form of CMT,” the researchers wrote. “IFB-088 has the unique potential to provide benefits to different CMT subtypes caused by different gene defects.”