Project Overview

Multisystem proteinopathy (MSP) is a devastating rare disease described by a cluster of diseases that affect the brain, bone, and muscle. Greater than 50 pathogenic genetic mutations of Valosin-containing protein (VCP) cause MSP. Unfortunately, patients with the mutation, even within the same family, can display any combination of the cluster of diseases, while also developing amyotrophic lateral sclerosis (ALS) and a multitude of other conditions. Rare diseases are often underfunded and thus understudied. This is complicated by the fact that VCP diseases are linked to so many mutations, which makes approaches that target the gene difficult, because a genetic treatment for each mutation is needed. Therefore, we first propose to look for non-mutation related changes in the VCP gene using patient DNA to identify a single targetable change for our small molecules called antisense oligonucleotides (ASOs). ASOs have been approved in other genetic diseases that have one or two mutations associated with them. ASOs can specifically target small genetic changes to prevent mutant proteins from being made.

However, there is a barrier between the blood and the brain that prohibits easy delivery of these drugs intravenously. For neurodegenerative disease, ASOs need to be injected directly into the spinal cord to access the brain and bypass the blood brain barrier. Consequently, we developed small carriers, called nanoparticles, that use proteins expressed in the liver that need to get to the brain to act like Trojan horses and carry ASOs across the blood brain barrier. In the other portion of this proposal, we aim to optimize our Trojan horses further to deliver our new ASOs. By mapping the VCP gene, we also hope to provide a better understanding of how the gene is regulated to develop new therapeutic strategies.

Principal Investigator

Dale Martin , University of Waterloo