PI: Hasan Akman, PhD
Institution: Columbia University Medical Center
Most of the genetic diseases caused by mutations alter the amino acid sequence of the protein affecting their function. In the case of APBD, the most common mutation substitutes the 329th amino acid tyrosine with serine. Although tyrosine in this location is not required for enzymatic activity, it affects either proper folding of GBE or degradation of GBE in an unknown mechanism. The second mutation we have discovered generates a splice acceptor site and traps the GBE1 mRNA after the 15th exon. The mRNA without proper exon 16 becomes unstable and gets degraded in the cell. It is fortunate that the location of this mutation allows us to block this splice acceptor site successfully by using antisense oligonucleotides (ASO). In patient skin fibroblast cells we were able to recover more than 40% of enzyme activity using antisense oligonucleotides (provided by IONIS pharmaceuticals, Carlsbad, CA) targeted to this Intronic mutation. Before setting up a clinical trial this approach has to be tried in a mouse model. However, mouse models we have generated contain classical APBD mutation and are not suitable models for ASO therapy. Therefore, we would like to test ASO treatment in the mouse model we are generating with human mutated sequence in intron 15 of the mouse Gbe1, and to show if the treatment slows down or reverses the course of the disease by restoring proper mRNA synthesis.