Factor Isolated That Regenerates Nerve Fibers - Previously Unknown Molecule Spur

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Factor Isolated That Regenerates Nerve Fibers - Previously Unknown

Molecule Spurs Regeneration In The Optic Nerve

http://www.medicalnewstoday.com/medicalnews.php?newsid=43428

Researchers at Children's Hospital Boston have discovered a naturally

occurring growth factor that stimulates regeneration of injured nerve

fibers (axons) in the central nervous system. Under normal

conditions, most axons in the mature central nervous system (which

consists of the brain, spinal cord and eye) cannot regrow after

injury. The previously unrecognized growth factor, called

oncomodulin, is described in the May 14 online edition of Nature

Neuroscience.

Neuroscientists Yuqin Yin, MD, PhD, and Larry Benowitz, PhD, who are

also on the faculty of Harvard Medical School, did their studies in

the optic nerve, which connects nerve cells in the eye's retina to

the brain's visual centers, and is often used as a model in studying

axon regeneration.

When oncomodulin was added to retinal nerve cells in a Petri dish,

with known growth-promoting factors already present, axon growth

nearly doubled. No other growth factor was as potent. In live rats

with optic-nerve injury, oncomodulin released from tiny sustained-

release capsules increased nerve regeneration 5- to 7-fold when given

along with a drug that helps cells respond to oncomodulin. Yin,

Benowitz and colleagues also showed that oncomodulin switches on a

variety of genes associated with axon growth.

Benowitz, the study's senior investigator, believes oncomodulin could

someday prove useful in reversing optic-nerve damage caused by

glaucoma, tumors or traumatic injury. In addition, the lab has shown

that oncomodulin works on at least one other type of nerve cell, and

now plans to test whether it also works on the types of brain cells

that would be relevant to treating conditions like stroke and spinal

cord injury.

The current study builds on work Benowitz, Yin and colleagues

published a few years ago. Studying the optic nerve, they found -

quite by accident - that an injury to the eye activated axon growth:

it caused an inflammatory reaction that stimulated immune cells known

as macrophages to move into the eye.

" To make this finding clinically useful, we wanted to understand what

was triggering the growth, so we could achieve nerve regeneration

without causing an injury, " Benowitz says.

Working in Benowitz's lab, Yin took a closer look and found that the

macrophages secreted an essential but as-yet unidentified protein.

Further studies revealed it to be oncomodulin, a little-known

molecule first observed in association with cancer cells.

" Out of the blue, we found a molecule that causes more nerve

regeneration than anything else ever studied, " Benowitz says. " We

expect this to spur further research into what else oncomodulin is

doing in the nervous system and elsewhere. "

For oncomodulin to work, it must be given along with an agent that

raises cell levels of cyclic AMP, a " messenger " that initiates

various cellular reactions. Increased cyclic AMP levels are needed to

make the oncomodulin receptor available on the cell surface.

A two-pronged approach Benowitz also notes that there is another side

to the nerve-regeneration problem: overcoming agents that act as

natural inhibitors of axon growth. These inhibitors are the subject

of intense study by several labs, including that of Zhigang He, PhD,

at Children's Hospital Boston.

In a study published in 2004, Benowitz and postdoctoral fellow

Dietmar Fischer, PhD, collaborated with He to combine both

approaches - overcoming inhibition and activating the growth state

(by injuring the lens of the eye) - and achieved dramatic optic-nerve

regeneration. Now that Benowitz has isolated oncomodulin, he believes

even greater regeneration is possible by combining it with agents

that counteract growth inhibitors.

" We're in the midst of an exciting era of research in nerve

regeneration, " Benowitz says. " There are a lot of promising leads in

the area of blocking molecules that inhibit regeneration. But to get

really strong regeneration, you also have to activate nerve cells'

intrinsic growth state. "

The study was funded by the National Eye Institute (part of the

National Institutes of Health), the Family Trust, the

European Commission, and Boston Life Sciences, Inc. The oncomodulin

technology has been licensed by Boston Life Sciences, Inc. (BLSI;

Hopkinton, Mass.), which is testing recombinant oncomodulin for

ocular indications in pre-clinical studies. BLSI has also licensed

other axon regeneration technologies developed at Children's.