Mouse Transcriptome Offers Hope to ALS Patients

Amyotrophic lateral sclerosis (ALS), more commonly referred to as Lou Gehrig's disease, is a condition where motor neuron function is lost progressively over time. ALS progression can ultimately lead to total paralysis and death. ALS is generally thought to occur around the age of 55, is more prevalent in Caucasian men, and is estimated to currently afflict 30,000 Americans.

Treatment of ALS is limited to one drug, rulizole, and its benefit has been described as modest. A new study published in the journal Nature Genetics assessed temporal transcriptional changes that occur in ALS progression using a mouse model. Furthermore, the study sought to expand current knowledge about potential therapeutic targets for ALS treatment.

The authors use the ALS mouse model to study what changes occur on the transcriptional level in this disease. Interestingly, genes involved in immune system activation were found to be perturbed in the ALS mouse. Specifically, co-stimulatory pathways that are involved in immune stimulation were found to be elevated. This finding was confirmed in humans as well, as 56% of ALS patients screened in the study had a similar increase in co-stimulatory signaling.

In other diseases where co-stimulatory pathways are implicated, such as graft versus host disease, treating with antibodies that block this type of signaling has a therapeutic benefit. For this reason, the authors treated the ALS mice with a CD40L monoclonal antibody that blocks co-stimulation and assessed disease severity. Treatment with the CD40L antibody delayed paralysis, helped maintain body weight, and extended lifespan after ALS symptoms started to appear in the mouse model. Treatment with this antibody also decreased motor neuron loss in the ALS mice.

ALS is a debilitating neurodegenerative disease that leads to paralysis and eventual death. This study is significant because it suggests that inhibition CD40L in ALS has a potential therapeutic benefit. The benefit of this approach will need to be verified in humans with ALS in clinical trials. Only one drug is currently approved for ALS treatment and this study hopefully opened the door for another potential therapy. Furthermore, this study exemplifies the potential use of transcriptional profiling in disease models to uncover novel therapeutic targets.

References:

Lincecum, JM., et, al. From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis. Nature Genetics. 2010 Mar 28. [Epub ahead of print].

What is ALS? ALS Association. http://www.alsa.org/als/what.cfm?CFID=5745645&CFTOKEN=f2590fa9cda27826-B58759E5-188B-2E62-809EB2B5FB76D1ED Accessed 3/28/2010.