BioWorld International Correspondent

LONDON - It could one day be possible to treat the inherited form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) with gene therapy, a study in an animal model of the disease suggested.

Researchers at Oxford BioMedica, of Oxford, UK, have prolonged the life of mice with a condition similar to ALS, using RNA interference to silence a mutant gene.

Alan Kingsman, chief executive of Oxford BioMedica, told BioWorld International that the approach could be developed to treat humans with the inherited form of ALS, although it would involve "heroic" numbers of injections into all muscle groups, probably taking place over a period of months.

Other inherited diseases might also be amenable to the same approach - but on two conditions: First, they would need to involve a genetic mutation that should be switched off in order to attain normality. Secondly, there would need to be a way to deliver the therapy to enough tissues to have the required effect. Kingsman thought that Huntingdon's disease and possibly some types of Alzheimer's disease might be suitable.

However, Oxford BioMedica is not planning to develop the therapy for patients. Kingsman said the project would not be commercially viable, although the company would, he said, give all possible help to any government or charity that wished to investigate the strategy further.

The company reported its work in the March 13, 2005, issue of Nature Medicine in a paper titled "Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model."

ALS, both sporadic and inherited, affects about five in every 100,000 people, usually in their 50s or 60s. It causes progressive deterioration of motor neurons and usually results in death within three to five years. Famous sufferers include the British scientist Stephen Hawking, who is still alive years after diagnosis and the U.S. baseball player Lou Gehrig, who died.

In the inherited form of ALS, known as familial ALS (FALS), there is a metabolic abnormality involving a protein called superoxide dismutase 1 (SOD1). The mutant protein is toxic to motor neuron cells.

The inherited form accounts for only 2 percent to 5 percent of patients, and in the remaining 95 percent to 98 percent, the cause of the disease remains unknown. No treatments are available for patients in either group.

Oxford BioMedica has developed a lentivirus vector for shuttling genes into cells. The vector, based on the equine infectious anemia virus, is marketed as LentiVector. The company wanted to prove to its potential pharmaceutical customers that LentiVector was an ideal technology for anyone who wanted to deliver interfering RNA into cells.

RNAi comprises small RNA molecules that bind to the messenger RNA for specific proteins, thus shutting down protein synthesis.

The paper in Nature Medicine reported how RNAi specific for the messenger RNA made by the gene that encodes the FALS mutant SOD1 was delivered, using LentiVector, into the motor neurons of mice that provide an animal model of ALS.

The virus had been further modified to make it express on its surface a protein from the rabies virus. That protein allows the rabies virus to enter motor neurons at the neuromuscular junction. Likewise, the rabies protein targets the lentivirus vector to the motor neurons that control the muscles that have been injected.

In Nature Medicine, Scott Ralph and colleagues from Oxford BioMedica described how levels of SOD1 fell by 40 percent in parts of the spinal cord, two weeks after the injections into the hind-limb muscles.

The animals used for the study overexpress a mutant form of human SOD1 that is known to cause FALS in humans. The animals usually start to show symptoms of disease at about 100 days, and die at about 140 days. However, treated animals showed a highly significant delay in the onset of motor symptoms, which began at about 230 days, and survived much longer, dying at about 265 days (p<0.0001 in both cases).

Kingsman speculated that, if translated into humans, results such as those might allow patients to double their life expectancy at diagnosis, from 3 to 5 years up to 6 to 10 years.

"It might even be feasible to cure patients if they had enough injections," he said. "It would take only a tiny fraction of the money the UK currently pours into academic medical research to develop this product."