Science Editor

Myelin damage is at the heart of multiple sclerosis (MS), and encouraging the regeneration of oligodendrocytes may be one therapeutic avenue to treat the disease. (See BioWorld Today, July 6, 2011.)

But such regeneration could also offer hope in another form of brain damage: neonatal brain damage as a result of low oxygen during birth.

Oligodendrocytes – the cells that form the insulating myelin sheath that wraps around neurons and allows rapid electrical conduction over long distances – are especially vulnerable to conditions of low oxygen. And when things go wrong during a birth, even for a relatively brief period of time, the effects can far outlast the actual crisis. A few minutes of oxygen deprivation can result in a lifetime of cerebral palsy or cognitive disabilities.

In fact, white matter injury is the most reliable indicator for preemies who will go on to develop severe cerebral palsy. And the incidence of such disabilities is increasing as more extremely premature babies survive.

Now, a team of scientists from the University of California at San Francisco has reported the involvement of a pathway in such myelin damage that is an old biotech industry acquaintance: the Wnt pathway.

Wnt is a cancer stem cell signaling pathway, and the subject of a Redwood City, Calif.-based OncoMed Pharmaceuticals Inc. and Bayer Schering Pharma AG collaboration. Others are also in the space, though drugging Wnt is a challenge to date. (See BioWorld Today, June 18, 2010.)

Lead author Steven Fancy, a postdoctoral researcher at UCSF, and his team published their new findings in the June 26, 2011, online issue of Nature Neuroscience.

They began by looking at brain tissue from premature babies who had died after sustaining brain injury, and found that they expressed the protein Axin2 at high levels in their oligodendrocyte precursors. In mouse models of neonatal brain injury, too, Axin2 RNA was expressed at high levels in the precursors – but not in mature oligodendrocytes. Axin2 knockouts had delayed myelin repair after an injury.

In both cell culture and mouse models of newborn brain injury, treatment with a small molecule that stabilizes Axin2 levels by preventing the protein from being degraded led to increases in the number of mature oligodendrocytes. XAV939 inhibits tankyrase, an enzyme that usually degrades Axin2. And because Axin2, in turn, is a "control mechanism for shutting off the pathway," the net result of Xav939 is an inactivated Wnt pathway.

Fancy said that promoting cell differentiation after myelin injury by shutting down Wnt signaling is in line with the known effects of Wnt. "In a lot of tumor situations, Wnt promotes proliferation, but also inhibits differentiation," he told BioWorld Today – and the latter is certainly true in the case of white matter injury.

In their experiments, the team delivered XAV939 directly to the damage sites.

"We haven't tested it systemically yet," Fancy said, acknowledging that such an approach might be fraught with risk, since Wnt signaling is "very much connected with colon tumors . . . systemic delivery of these [drugs] has to be done with extreme caution."

But from a cell biology standpoint, the bottom line is that "by inhibiting [the Wnt] pathway with a drug you can produce a better white matter repair."

The team's current work focuses on neonatal brain injury. But "we showed some time ago that there was a role for the Wnt pathway in multiple sclerosis," Fancy said. "In both situations, they seem to have white matter damage, which they try to repair."

But they can't get there from here: Oligodendrocyte precursors are stalled in their differentiation – and "the Wnt pathway seems to be responsible for this block."

Even more generally, Wnt up-regulation is "quite a general response to oligodendrocyte damage," and so the same mechanisms might also be operating in spinal cord injury due to accidents.

Fancy and his team did not look at that possibility explicitly, and Fancy cautioned that in accidental injury, neurons as well as white matter contribute to the problems with regeneration. But the lab of senior author David Rowitch is collaborating with another lab to see whether such mechanisms play a role in spinal cord injuries due to accidents.