Functional Genomics: Centralised capacity to develop functional genomics for paediatric precision medicine

We used functional genomics – the study of how the ‘omics’ work together to influence disease – to improve children’s screening and diagnosis and personalise clinical management.

As a result of our work, we introduced novel treatment paradigms, including gene and cell therapies, for genetic diseases (blinding eye diseases, inborn errors of metabolism, muscular diseases and telomere-related blood disorders and cancers).

We boosted NSW’s stem cell capabilities to include stem cell production, organoid and cell-based disease modelling and genetic modification, and we enhanced NSW’s genome editing capacity by establishing the Vector and Genome Engineering Facility.

Lead Investigators

• Professor Ian Alexander
  Head, Gene Therapy Unit, Children’s Medical Research Institute (Australia)
• Professor Patrick Tam
  Head, Embryology Unit, Children’s Medical Research Institute (Australia)

Research Team

• Dr Anai Gonzalez Cordero, Children’s Medical Research Institute (Australia)
• Professor Robyn Jamieson, Children’s Medical Research Institute (Australia)
• Professor Tracy Bryan, Children’s Medical Research Institute (Australia)
• Dr Leszek Lisowski, Children’s Medical Research Institute (Australia)

• Children’s Medical Research Institute (Australia)
• Kids Research, Sydney Children’s Hospitals Network (Australia)
• Children’s Cancer Institute (Australia)
• University of Sydney (Australia)
• University of Technology Sydney (Australia)
• University of Adelaide (Australia)
• City of Hope Center for Gene Technology (USA)
• University of Lisbon (Portugal)
• University Medical Center Utrecht (Netherlands)
• Australian Functional Genomics Network (https://www.functionalgenomics.org.au/)

Impact Report 2023

Patient story Emmanuel

Occular Gene and Cell Therapies NSW Health

Functional genomics capacity and capability

Nelson N, Feurstein S, Niaz A, Truong J, Holien JK, Lucas S, Fairfax K, Dickinson J, Bryan TM. Functional genomics for curation of variants in telomere biology disorder associated genes, a systematic review. Genetics in Medicine. 2022 Dec 7.

Okada T, McIlfatrick S, Hin N, Aryamanesh N, Breen J, St John JC. Mitochondrial supplementation of Sus scrofa metaphase II oocytes alters DNA methylation and gene expression profiles of blastocysts. Epigenetics & chromatin. 2022 Dec;15(1):1-20.

Connolly K, Gonzalez-Cordero A. Modelling inner ear development and disease using pluripotent stem cells–a pathway to new therapeutic strategies. Disease Models & Mechanisms. 2022 Nov 1;15(11):dmm049593

Bouasker S, Patel N, Greenlees R, Wellesley D, Taie LF, Almontashiri NA, Baptista J, Alghamdi MA, Boissel S, Martinovic J, Prokudin I. Bi-allelic variants in WNT7B disrupt the development of multiple organs in humans. Journal of Medical Genetics. 2022 Jul 5.

Fernando M, Lee S, Wark JR, Xiao D, Lim BY, O’Hara-Wright M, Kim HJ, Smith GC, Wong T, Teber ET, Ali RR. Differentiation of brain and retinal organoids from confluent cultures of pluripotent stem cells connected by nerve-like axonal projections of optic origin. Stem Cell Reports. 2022 Jun 14;17(6):1476-92.

Mediati DG, Wong JL, Gao W, McKellar S, Pang CN, Wu S, Wu W, Sy B, Monk IR, Biazik JM, Wilkins MR. RNase III- CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3′ UTR required for intermediate vancomycin resistance. Nature communications. 2022 Jun 22;13(1):1-5.

O’Hara-Wright M, Mobini S, Gonzalez-Cordero A. Bioelectric Potential in Next-Generation Organoids: Electrical Stimulation to Enhance 3D Structures of the Central Nervous System. Front Cell Dev Biol. 2022 May 17;10:901652. doi: 10.3389/fcell.2022.901652. PMID: 35656553; PMCID: PMC9152151.

Westhaus A, Cabanes-Creus M, Jonker T, Sallard E, Navarro RG, Zhu E, Baltazar Torres G, Lee S, Wilmott P, Gonzalez-Cordero A, Santilli G. AAV-p40 bioengineering platform for variant selection based on transgene expression. Human Gene Therapy. 2022 May 6.

West EL, Majumder P, Naeem A, Fernando M, O’Hara-Wright M, Lanning E, Kloc M, Ribeiro J, Ovando-Roche P, Shum IO, Jumbu N. Antioxidant and lipid supplementation improve the development of photoreceptor outer segments in pluripotent stem cell-derived retinal organoids. Stem cell reports. 2022 Apr 12;17(4):775-88.

Chahine Karam F, Loi TH, Ma A, Nash BM, Grigg JR, Parekh D, Riley LG, Farnsworth E, Bennetts B, Gonzalez- Cordero A, Jamieson RV. Human iPSC-Derived Retinal Organoids and Retinal Pigment Epithelium for Novel Intronic RPGR Variant Assessment for Therapy Suitability. Journal of personalized medicine. 2022 Mar 21;12(3):502.

Chan DL, Rudinger-Thirion J, Frugier M, Riley LG, Ho G, Kothur K, Mohammad SS. A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders. Brain and Development. 2022 Feb 1;44(2):142-7.

Bournazos AM, Riley LG, Bommireddipalli S, Ades L, Akesson LS, Al-Shinnag M, Alexander SI, Archibald AD, Balasubramaniam S, Berman Y, Beshay V. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants. Genetics in Medicine. 2022 Jan 1;24(1):130-45.

Niaz A, Truong J, Manoleras A, Fox LC, Blombery P, Vasireddy RS, Pickett HA, Curtin JA, Barbaro PM, Rodgers J, Roy J. Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder. Blood Advances. 2022 Apr 29.

Xiao D, Kim HJ, Pang I, Yang P. Functional analysis of the stable phosphoproteome reveals cancer vulnerabilities. Bioinformatics. 2022 Apr 1;38(7):1956-63.

Aryamanesh N. A Reproducible and Dynamic Workflow for Analysis and Annotation of scRNA-Seq