Rett syndrome is a debilitating genetic disorder of the brain, resulting in very severe physical and cognitive disability. It is mostly caused by mutations (errors in the genetic code), in the “MECP2” gene, a gene that is vital for normal brain function.
Given the highly complex nature of the brain, developing treatments for genetic brain disorders such as Rett syndrome has always been challenging. While multiple studies have led to a better understanding of the disorder, none have yet led to a new treatment or cure for the disease.
The Molecular Neurobiology Research laboratory, headed by Dr Wendy Gold, is focused on developing and applying advanced gene-editing technologies for the treatment of Rett syndrome.
The Molecular Neurobiology Research laboratory is focused on developing and applying advanced gene-editing technologies for the treatment of Rett syndrome.
Classical gene therapy involves replacing a defective gene with a healthy one. This is most commonly done by removing cells from the body, using genetic engineering techniques to target and change the defective sequences in the DNA, and then reinserting the cells into the body.
When working with brain disorders, however, this approach is not viable due to the complex architecture of the brain and the inability of brain cells to divide. Thus it is not possible to remove brain cells, correct their defective sequences and place them back in the brain.
Using innovative gene-editing tools such as “CRISPR-Cas9”, the Molecular Neurobiology Research team are exploring an avenue of gene therapy beyond this conventional approach. This involves developing an intravenous therapy incorporating CRISPR-Cas9 that can cross the blood-brain-barrier, the brain’s gate-keeper, and specifically target the mutated gene in affected cells. Replacing the disease-causing mutation with a normal copy of the gene would result in a permanently edited copy of the gene, and the potential to provide a life-long cure for patients with Rett syndrome.
The research team
The research goals of my lab are to better understand the underlying molecular mechanisms of Rett syndrome and to develop gene-editing techniques for gene therapy. More information can be found on Wendy's University of Sydney profile page.
> Other Research Team Members
• Ally Boyling, Honours student
• Andre Gretch, Honours student
Rett Syndrome: A Genetic Update and Clinical Review Focusing on Comorbidities. Gold, W., Krishnarajy, R., Ellaway, C., Christodoulou, J. (2018). ACS Chemical Neuroscience, 9(2), 167-176.
A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction. Gold, W., Sobreira, N., Wiame, E., Marbaix, A., Van Schaftingen, E., Franzka, P., Riley, L., Worgan, L., Hubner, C., Christodoulou, J., Ades, L. (2017). American Journal of Medical Genetics, Part A, 173(8), 2246-2250.
Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. Nafisinia, M., Riley, L., Gold, W., Bhattacharya, K., Broderick, C., Thorburn, D., Simons, C., Christodoulou, J. (2017). PloS One, 12(6), 1-12.
Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. Nafisinia, M., Sobreira, N., Riley, L., Gold, W., Uhlenberg, B., Weib, C., Boehm, C., Prelog, K., Ouvrier, R., Christodoulou, J. (2017). European Journal of Human Genetics, 25(10), 1134-1141.
Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease. Alodaib, A., Sobreira, N., Gold, W., Riley, L., Van Bergen, N., Wilson, M., Bennetts, B., Thorburn, D., Boehm, C., Christodoulou, J. (2017). European Journal of Human Genetics, 25(1), 79-84.