Animal Studies Funded by The ALS Association March 13, 2005
Researchers from the Swiss Federal Institute of Technology led by Patrick Aebischer, M.D., who is funded through the investigator initiated program of ALSA and French collaborators, reported March 13 in an advance online publication for the April, 2005 issue of Nature Medicine that ALS mice injected with the RNA silencing therapeutic retained motor skills. A virus engineered to no longer be infectious, called a vector, brought the therapeutic RNA inside cells. The treated mice, injected at 40 days old prior to disease onset, were better able to maintain swimming in a laboratory test, for about 20 days longer than untreated animals. At 120 days of age, mutant SOD1 mice take twice the time to swim to a platform as do normal mice. The treated mice had an improved swimming time of 50% as compared with the untreated group.
The treatment also salvaged motor neurons supplying the hind limb muscle. RNA silencing produced mice that had only a 50% loss of motor neurons, at a time that untreated mutant mice showed a 70% loss of their motor neurons.
Treatment saved hind limb muscle mass, and more neuronal fibers remained in the supplying nerve. The injection had been targeted to the area of spinal cord controlling this hind limb.
Mutant SOD1 production was suppressed in neighboring glial cells as well as motor neurons. This finding bodes well for ALS, as these cells have been shown to influence survival of motor neurons.
The Swiss and French researchers showed that the RNA molecule that they constructed lowered the amount of SOD1 made by cells while growing in lab dishes. Other genes continued to produce proteins. This highlights the ability of the treatment to specifically shut off production of SOD1.
“An attractive therapeutic approach is therefore to target the cause of the disease by reducing levels of mutant SOD1 expression in the spinal cord,” write the researchers in their report. They added that the strategy could work for other disorders, such as Huntington’s disease, and Parkinson’s disease, where a mutant protein is producing toxic effects.
A British company, Oxford Biomedica Ltd. in Oxford, U.K., also published in the advance online for the April issue of Nature Medicine that a lentiviral vector successfully delivers an RNA silencing construct to treat ALS mice. The researchers led by Mimoun Azzouz, Ph.D., write that the treatment delayed the onset of ALS symptoms “by more than 100% and extended lifespan by nearly 80% of their normal life span.” This treatment worked by injection into the muscles that are weakened in ALS in the mice, and in people. Mice were treated at seven days of age. “In follow up studies it will be important to determine whether this approach will show a similar significant benefit at time of onset, a time more similar to the clinical setting,” commented Bruijn.
After intramuscular injection in the mouse model, the delivery system is transported back to the cell body, exploiting a normal process of retrograde transport in motor neurons. The unlimited production of the RNAi molecule within the cell body leads to the reduction of mutant SOD1 in spinal motor neurons and surrounding cells.
Bruijn noted that “several other groups are involved in similar efforts and the collective data will help move this therapy more rapidly forward for clinical application.”
