La Trobe research offers new hope for MS therapy

It's too early to announce a new dawn, but there's a distinct glow on one of neuroscience's darkest horizons. The enigma of the paralysing central nervous system disorder, multiple sclerosis, may be nearing solution.

A study by researchers in La Trobe University's neuroimmunology laboratory, published online in Nature Neuroscience on June 7, strengthens suspicions that MS researchers have been focusing on the wrong mechanism.

MS is a form of autoimmune disease, and researchers have long believed its creeping paralysis results when immune-system cells attack the myelin basic protein that sheaths and insulates nerve fibres in the spinal cord. By exposing the nerve axons, the resulting lesions were thought to short-circuit the electrical impulses that relay the brain's instructions to the muscles.

The La Trobe research team, led by Dr Tara Karnezis, a research fellow in the laboratory of renowned MS researcher Prof Claude Bernard, has found evidence that the damage goes deeper than damage to the myelin sheath. The researchers believe the lesions actually sever the axons of injured neurons, rather than just impairing their function.

The myelin basic sheath grows out from specialised support cells called oligodendrocytes. When the sheath is damaged, the oligodendrocytes secrete a signalling protein, Nogo A, which compounds the damage by preventing the damaged axons sprouting new neuritis to re-establish their lost connections.

Karnezis -- now at Stanford University -- wondered if switching off Nogo A could prevent further nerve damage in a mouse model that reproduces all the symptoms of human multiple sclerosis.

She and her colleagues vaccinated the mice with a peptide antigen derived from the Nogo A protein, before treating them with a drug that induces MS-like damage to their spinal-cord nerves.

Bernard described the results as dramatic, and unexpected. "We had expected the animals to develop MS-like disease, but to recover more quickly than normal," he said. "In fact, the vaccine suppressed the disease and significantly reduced the pathology."

Karnezis then obtained a transgenic Nogo A knockout mouse from Dr Mark Levine's MS research group at Stanford -- the two research groups collaborate. Efforts to induce MS-like damage in the knockout mice produced the same result.

"They showed a tremendous reduction in susceptibility to the disease," Bernard said. "The implication is that this molecule might be an important determinant in the development of MS. If so, it would be wonderful.

"It would explain many things about MS -- it would establish a connection between Nogo A and inhibition of the development of new neuritis in damaged nerves."

Karnezis' team then tried a technique already used experimentally by researchers investigating the possibility of treating paralysing spinal-cord injuries. They injected their MS mice with purified antibodies directed against the same Nogo A peptide could relieve established MS-like symptoms. The mice recovered.

Bernard and his colleagues are performing further experiments to determine whether the MS mice grow new neuritis when Nogo A is suppressed. "If that is the case, it would be very exciting," Bernard said.

Bernard recently described his team's findings at an MS research conference in the US, where he learned that several pharmaceutical companies are already experimenting with soluble receptors for Nogo A to promote nerve regeneration in MS.

The soluble receptors would intercept the Nogo A signalling protein before it could inactivate neurite re-sprouting from damaged nerves. Bernard believes if the soluble-receptor approach works, it would be an ideal therapy for MS.