Developing and Testing Therapeutic Strategies for ALS Using the Transgenic Mouse Models

We conduct in vivo therapeutic trials in mouse models for ALS. Our recent effort has focused on delivering RNAi therapy for familial ALS caused by mutations in SOD1 gene. We first expressed a mutant allele-specific artificial micro RNA (amiR-SOD1) in vivo and demonstrated that allele-specific silencing is efficacious in knocking down mutant SOD1 and slowdown the disease progression (Xia et al., 2006). We then tested various approaches to deliver the amiR-SOD1. Our early experiments showed that both adenoviral vectors and chemically modified siRNAs can deliver silencing against the mutant gene expression but those strategies were limited by their toxicity (Wang et al., 2008; Wu et al., 2009). Recently we have been focusing on adenoassociated viral (AAV) vector-based strategies to deliver silencing against the mutant gene expression. We have developed method to deliver AAV transduction throughout the entire spinal cord by a single intrathecal injection, or to wide areas of the forebrain by a single injection of AAV into the third ventricle. We used this delivery method to express amiR-SOD1 in the spinal cord and shown efficacy in slowing the disease progression (Wang et al., 2014). Recently we have simplified the method by achieving efficient transduction throughout the spinal cord using a lumbar puncture injection procedure (Guo et al., 2016). Currently we are further optimizing the delivery method for AAV delivery and testing various therapeutic molecules in the ALS mouse models.