Histone Deacetylase 3 Inhibits Peripheral Myelinogenesis

An experimental molecular therapy that restores insulation on peripheral nerves in mice, improves limb function, and results in less observable discomfort, indicates a study led by scientists at Cincinnati Children’s Hospital Medical Center.

When the body attacks its own healthy tissues in an autoimmune disease, peripheral nerve damage handicaps people and causes persistent neuropathic pain when insulation on healing nerves doesn’t fully regenerate. Unfortunately, there are no effective ways to treat the condition.

To identify possible therapies, the international team of investigators performed small-molecule epigenetic screening for compounds that inhibit enzymes involved in epigenetic changes on chromosomes.

Accelerated Myelin Formation

Epigenetic changes alter how gene activity in cells is regulated. The authors identified small molecular inhibitors already used to treat certain cancers and tested them in experimental treatments on mice with injured sciatic nerves.

The molecular compounds target the enzyme HDAC3 (histone deacetylase 3). Study data show that HDAC3 inhibits regenerating insulation on recovering peripheral nerves.

“Remarkably, temporary inhibition of HDAC3 robustly accelerated the formation of myelin that helps insulate peripheral nerves. This promoted functional recovery in the animals after peripheral nerve injury,”

said principal investigator is Q. Richard Lu, PhD, director of the Cincinnati Children’s Brain Tumor Center.

Signal Relays

The peripheral nervous system relays signals from the brain and spinal cord (the central nervous system) to limbs and organs. HDAC3 is an enzyme found in humans and mice. Its usual job in peripheral nerve formation is to act as a molecular brake on the production of the myelin coating by Schwann cells.

After peripheral nerve injury, HDAC3 initiates epigenetic changes to chromosomes and gene regulation that excessively restrict myelin regeneration. This results in nerve insulation that is too thin or not totally formed, blocking or slowing signals between the spinal cord, extremities and organs.

Researchers carefully timed their targeted treatments when inhibiting HDAC3, treating the mouse models of nerve injury only during a critical phase of nerve regeneration. This resulted in the right amount of re-myelination to restore normal function in the animals.

Getting the timing right on transient treatment is critical, Lu says.

Researchers show that blocking HDAC3 for too long allows myelin to overgrow and cause excessively thick insulation. This also can lead to functional problems in extremities, according to study data.

Next Steps

Translating data in the current study to clinical application in human patients will require extensive additional research, Lu says.

Now that the prospective therapy has been successfully tested in mice, researchers are exploring additional research in animal models that more closely mimic the repair of injured peripheral nerves in people. This includes looking specifically at some demyelinating diseases that affect the central nervous system, such as multiple sclerosis.

Lu said this work will allow scientists to replicate and verify their findings in mice and other laboratory models. They also will be able to test possible dosing levels. If results are positive, Lu said researchers could pursue possible Phase I clinical trials in patients having deficient myelin in their peripheral and central nervous systems.

The study was funded in part by the US National Institutes of Health and the National Multiple Sclerosis Society.

Xuelian He, Liguo Zhang, Luis F Queme, Xuezhao Liu, Andrew Lu, Ronald R Waclaw, Xinran Dong, Wenhao Zhou, Grahame Kidd, Sung-Ok Yoon, Andres Buonanno, Joshua B Rubin, Mei Xin, Klaus-Armin Nave, Bruce D Trapp, Michael P Jankowski & Q Richard Lu
A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration
Nature Medicine doi:10.1038/nm.4483

Image: inhibiting an enzyme called HDAC3 in mice increases the expansion of Schwann cells (green). Credit: Cincinnati Children’s