This strategy, reported online on December 15 in advance of print publication in the January 2006 issue of the Journal of Clinical Investigation, holds promise for many other disorders characterized by nerve degeneration due to loss of function of a known gene.

Hereditary spastic paraplegia (HSP), a neurodegenerative disorder caused by progressive loss of sensory and skeletal muscle nerve fibers (axons), is characterized by weakness, spasticity, and impaired function of the lower limbs. The disorder is often due to mutations in the gene encoding the paraplegin protein. HSP sufferers are ultimately confined to a wheelchair, and currently there is no cure for the disease. In the current study, Rugarli and colleagues have shown that a one-time delivery of normal paraplegin by a viral vector to the spinal motor neurons of mice with HSP, before the onset of symptoms, was able to save axons from degeneration for up to 10 months.

Delivery of this mitochondrial energy-dependent protease improved motor function in the mice and these data show that delivery of an intracellular protein to spinal motor neurons by gene transfer may be useful not only for the treatment of HSP patients but also for those individuals with other forms of peripheral nerve damage of known genetic origin.

jci/

Commenting on the frequency of this protection mechanism, Dr. Peter Horak, a co-author of the paper, said: "We established that 6% of the cancer cells examined actually exhibited both mechanisms. In all, more than 65% of the 68 cancer cells examined have at least one mechanism that allows them to elude the immune surveillance mediated by TRAIL."

Hot on the Therapy TRAIL

The team also found that increased concentrations of TRAIL appeared in the tissue samples of advanced stage patients, and were particularly prevalent in healthy tissue close to the tumour. Prof. Krainer remarks: "It was previously anticipated that TRAIL is mainly produced by the cancer cells themselves. Healthy ovarian tissue does not normally produce TRAIL. The presence of TRAIL in this healthy tissue, observed by us for the first time, is most probably a reaction to the development of the tumour. The body is fighting back. And our data shows that patients who produce TRAIL in this tissue have a higher life expectancy." This last finding suggests that TRAIL could have therapeutic uses.

Two innovative therapeutic approaches of this kind are indeed currently being developed. Both are based on the controlled activation of TRAIL-binding receptors. The data published in Clinical Cancer Research provides important information on the potential effectiveness of these strategies, since it will depend both on the production of this signal molecule and on the newly discovered protection mechanisms.

meduniwien.ac.at