WF Blue Project
WF Blue Members
Project Overview
Tay Sachs is a genetic disorder due to the inheritance of two autosomal recessive alleles. It results in the degeneration of mental and physical capacities, starting at 6 months of age and usually leading to death by four years of age. Tay Sachs is due to a chromosomal mutation in the HEXA gene of chromosome 15, a common mutation is the product of a 4 base pair insertion in exon 11. Prior studies have been done in mice and humans exhibiting Duchenne muscular dystrophy in which oligonucleotide sequences bind to an exon, inducing exon-skipping when splicing occurs. This exon skipping restores the original reading frame and helps to counteract the original mutation effects. Such a system of oligonucleotide induced exon-skipping could also aid in restoring the original reading frame in certain Tay Sachs mutations.
Background Information
The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase Myerowitz, et al., 1988
This paper describes how a common mutation in Tay-Sachs is a 4 base pair insertion in exon 11 that results in a splice junction defect and pre-mature termination of beta-hexosaminidase.
Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide Fletcher, et al., 2005
Studies were performed on mdx mice, or mice exhibiting a nonsense mutation in exon 23 of the dystrophin gene. Antisense oligonulceotides were administered to the mice, along with 2-O-methylphosphorothioate and peptide nucleic acid
Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study Cirak, et al., 2011
Through this study patients with DMD were treated using oligonucleotides. This study showed an increase in dystrophin levels.
