This paper from Zhong et al. assesses the effect of activated protein C (APC) therapy on ALS mice expressing hSOD1G93A. The authors show that daily i.p. injection of APC increases survival in a dose-dependent manner. The survival was increased by more than 25 days, which is impressive for this rapid progressing and broadly used ALS mouse model. In addition, the treatment was started after onset (around one week after the onset defined by weight peak), making the result even more important and significant, especially when one thinks about potential therapeutic use. Indeed, since most of the ALS cases are sporadic and of unknown origin, patients are diagnosed after symptoms begin. Therefore, a drug for ALS should have the potential of slowing down the disease after onset.

The result of the treatment is, therefore, impressive, but even more surprising is the finding of the pathway by which APC leads to slowing of disease progression. While the drug was used to determine if reducing the blood spinal cord barrier leakage (previously observed in this model by the same Zlokovic and...  Read more

This paper from Zhong et al. assesses the effect of activated protein C (APC) therapy on ALS mice expressing hSOD1G93A. The authors show that daily i.p. injection of APC increases survival in a dose-dependent manner. The survival was increased by more than 25 days, which is impressive for this rapid progressing and broadly used ALS mouse model. In addition, the treatment was started after onset (around one week after the onset defined by weight peak), making the result even more important and significant, especially when one thinks about potential therapeutic use. Indeed, since most of the ALS cases are sporadic and of unknown origin, patients are diagnosed after symptoms begin. Therefore, a drug for ALS should have the potential of slowing down the disease after onset.

The result of the treatment is, therefore, impressive, but even more surprising is the finding of the pathway by which APC leads to slowing of disease progression. While the drug was used to determine if reducing the blood spinal cord barrier leakage (previously observed in this model by the same Zlokovic and Cleveland group (see Zhong et al., 2008) would be of benefit, the authors found that the beneficial effect of APC was linked to the downregulation of SOD1. However, they elegantly showed, by using a Cre/Lox approach, that downregulating SOD1 expression in the endothelial cells had no effect on the disease. The effect most likely came from downregulation of SOD1 in motor neurons and microglial cells (and probably astrocytes, not tested), as they showed by using laser microdissection and cell isolation.

APC slowed the disease progression, including motor neuron denervation and microglial activation. It would also be interesting to know if at the same disease stage microglial cells are less activated after APC treatment, leading to downregulation of mutant SOD1 in microglia and motor neurons.

These results make APC a potential candidate for therapies, but caution should be paid to potential peripheral effects. Indeed, in transgenic mice overexpressing human SOD1, APC downregulated both the expression of the human transgene and the endogenous mouse protein. However, nothing is known about the effect of downregulating SOD1 in humans. Since SOD1 acts as a radical oxygen species (ROS) scavenger, one could argue that in any neurodegenerative disease when ROS get produced, downregulating the expression of scavenging proteins might have a detrimental impact. In addition, downregulating SOD1 in Schwann cells by the Cre/Lox approach showed an acceleration of the disease in ALS mice (Lobsiger et al., 2009). Therefore, downregulating SOD1 outside of the CNS might have a negative impact on the disease, and the balance between the positive and the potential negative effect of SOD1 downregulation would have to be evaluated.

This work pertains to the major question about the effect of any drug tested in ALS mice. This model has been criticized in recent years because results obtained in the mice are not recapitulated in clinical trials. Several issues could, of course, be at play, the major one being that mouse biology is different from human biology. But additionally, it is important to look at the type of trial in the mouse that one would like to bring to the clinical. As previously mentioned, drugs in humans have to be used after the symptoms of ALS appear; therefore, it is very important, as in this study, to try the drug in these same conditions in the mouse. Furthermore, this new study now adds another point to be considered, that is, the potential of the drug to act directly on the expression of the mutant protein causing the disease.

Finally, it would, of course, be very interesting to try APC in other models to see 1) the effect of downregulating SOD1 in models that do not express mutant SOD1 (for other neurodegenerative diseases or models with other mutations responsible for ALS, such as TDP43); 2) the potential participation of wild-type SOD1 aberrant species in motor neuron degeneration; and 3) the actual contribution of APC’s effect on the blood-brain barrier.

View all comments by Severine Boillee