Our research

Our experts are engaged in a number of studies focused on the diagnosis, characterisation and treatment of individual leukodystrophies.

Patient Registry

Our team maintains a confidential research database of information about people with leukodystrophies and white matter disorders in Australia. These materials support the program’s basic science and clinical research efforts and allow our researchers to make meaningful advances in the diagnosis and treatment of leukodystrophies.

Diagnostic Programs

The Australian Leukodystrophy Clinical and Research Program collaborates on research projects that may be able to provide clinical and research based genomic testing for undiagnosed leukodystrophy and white matter disorder patients.

Clinical trials

Clinical trials are research studies designed to evaluate whether new drugs or other medical interventions are safe and effective in individuals with a specific medical diagnosis.

See below for a list of actively enrolling clinical trials where the Royal Children’s Hospital/Murdoch Children’s Research Institute is a trial site:

A Study to Evaluate the Safety and Efficacy of ION373 in patients with Alexander Disease (AxD)


Disease modelling and pre-clinical testing

The Translational Neuroscience Facility – CNS Gene Therapy Group at UNSW Sydney

This facility is led by Prof. Matthias Klugmann and Dr. Dominik Fröhlich, which investigates the molecular mechanisms of normal and pathological functions of neurons and myelin-forming cells in the central nervous system. The main focus is on a group of neurological disorders termed leukodystrophies – genetic diseases of the brain white matter associated with an early onset and substantial mortality in children. Our goal is to establish gene therapy strategies for leukodystrophies and related neurological disorders.

The first step in understanding these devastating conditions is to establish accurate, rodent disease models, which enable us to study the underlying pathophysiology and to explore novel therapeutic approaches. Once established, we leverage these models to develop new and innovative gene therapy strategies. We have a long-standing interest in adeno-associated virus (AAV) as gene therapy vectors and as tools in basic research.

We are developing the current AAV platform in two directions:

  1. To achieve widespread and stable gene expression in the CNS following intracranial or systemic delivery; and
  2. To overcome the inherent neurotropism of AAV for targeting specific CNS cell populations including glia.

Our research group employs state-of-the-art techniques, including behavioural testing, neurogenetics, molecular biology, histology and neuroimaging to characterise disease models and assess the therapeutic outcomes of gene therapy.

The Stem Cell Engineering Group at the Australian Institute for Bioengineering and Nanotechnology (AIBN) at the University of Queensland

This group is led by Prof. Ernst Wolvetang. By discovering how gene mutations and pathogens interfere with the development and function of the human brain our goal is to identify and test therapeutics that can improve health outcomes for patients.

Our approach is to reprogram blood or skin cells into so-called induced pluripotent stem cells that capture the genetic make-up of the patient. We next turn these pluripotent patient specific stem cells into a variety of neuronal cell types and brain organoids that mimic the development, architecture and function of specific regions of the human brain. This next provides us insight into how and when genetic mutations derail human brain development or function, and enables the screening of drugs.

We employ a range of cutting-edge technologies such as single cell RNAseq to interrogate the gene expression make-up of individual cells within the patient specific brain organoids, multi-electrode arrays to measure the activity and connectivity of neurons, and advanced imaging approaches and state-of-the-art robotics to identify disease features or screen drugs and other therapeutics such as AAV-based gene therapy.

Dr Mohammed Shaker applies this human stem cell based functional genomics approach to a range of genetic childhood white matter diseases such as Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL).



Dual-function AAV gene therapy reverses late-stage Canavan disease pathology in mice. Fröhlich D, Kalotay E, von Jonquieres G, Bongers A, Lee B, Suchowerska AK, Housley GD, Klugmann M. Front. Mol. Neurosci. 2022.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services. Stutterd C, Vanderver A, Lockhart P, Helman G, Pope K, Uebergang E, Love C, Delatycki M, Thornburn D, Mackay M, Peters H, Kornberg A, Patel C, Rodriguez-Casero V, Waak M, Silberstein J, Sinclair A, Nolan M, Field M, Davis M, Fahey M, Scheffer I, Freeman J, Wolf N, Taft R, van der Knaap M, Simons C, Leventer R. European Journal of Medical Genetics 2022. 65(9):p.104551.

Developmental delay and late onset HBSL pathology in hypomorphic Dars1M256L. Klugmann M, Kalotay E, Delerue F, Ittner LM, Bongers A, Yu J, Morris MJ, Housley GD, Fröhlich D. Neurochem Res. 2022 Mar 31.

Robust and Highly Reproducible Generation of Cortical Brain Organoids for Modelling Brain Neuronal Senescence In Vitro. Shaker, M. R., Hunter, Z. L., Wolvetang, E. Vis. Exp. (183), e63714, doi:10.3791/63714 (2022).

Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types. Shaker M, Kahtan A, Prasad R, Lee J, Pietrogrande G, Leeson H, Sun W, Wolvetang E and Sionchak A. Front. Cell Dev. 2022;10.

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants. Stellingwerff, M, Nulton, C, Helman, G, Roosendaal, S, Benko, W, Pizzino, A, Bugiani, M, Vanderver, A, Simons, C, van der Knaap, M. Neuropediatrics. 2022


A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Ghosh SG, Scala M, Beetz C, Helman G, Stanley V, Yang X, et al. European Journal of Human Genetics. 2021;29(2):271-9.

Cerebral Microangiopathy in Leukoencephalopathy With Cerebral Calcifications and Cysts: A Pathological Description. Helman G, Viaene AN, Takanohashi A, Breur M, Berger R, Woidill S, et al. Journal of child neurology. 2021;36(2):133-40.

Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10. Helman G, Compton AG, Hock DH, Walkiewicz M, Brett GR, Pais L, et al. Human mutation. 2021;42(1):19-24.

The Leukodystrophies HBSL and LBSL—Correlates and Distinctions. Muthiah A, Housley GD, Klugmann M, Fröhlich D. Frontiers in cellular neuroscience.2021;14(478).

Embryonal Neuromesodermal Progenitors for Caudal Central Nervous System and Tissue Development. Shaker, MR., Lee, JH., Sun, W. System and Tissue Development. J Korean Neurosurg Soc 2021.

Rapid and Efficient Generation of Myelinating Human Oligodendrocytes in Organoids. Shaker MR, Pietrogrande G, Martin S, Lee J-H, Sun W, Wolvetang EJ. Frontiers in cellular neuroscience. 2021;15(72).

Klotho inihibits neuronal senescence in human brain organoids. Shaker, MR, Aguado J, Chaggar, HK, Wolvetang E. npj Aging and Mechanisms of Disease 2021;7:18

Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy. Helman G, Zerem A, Almad A, Hacker JL, Woidill S, Sase S, LeFevre AN, Ekstein J, Johansson MM, Stutterd CA, Taft RJ, Simons C, Grinspan JB, Pizzino A, Schmidt JL, Harding B, Hirsch Y, Viaene AN, Fattal-Valevski A, et al. Pediatr Neurol. 2021. 

Expanded phenotype of AARS1-related white matter disease. Helman G, Mendes MI, Nicita F, Darbelli L, Sherbini O, Moore T, Derksen A, Amy Pizzino, Carrozzo R, Torraco A, Catteruccia M, Aiello C, Goffrini P, Figuccia S, Smith DEC, Hadzsiev K, Hahn A, Biskup S, Brösse I, et al. Genet Med. 2021. 


L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism. Das A, Fröhlich D, Achanta LB, Rowlands BD, Housley GD, Klugmann M, et al. Neurochemical research. 2020;45(6):1438-50.

A Hypomorphic Dars1 (D367Y) Model Recapitulates Key Aspects of the Leukodystrophy HBSL. Fröhlich D, Mendes MI, Kueh AJ, Bongers A, Herold MJ, Salomons GS, et al. Frontiers in cellular neuroscience. 2020;14:625879.

RNA sequencing identifies a cryptic exon caused by a deep intronic variant in NDUFB10 resulting in isolated Complex I deficiency. Helman, G, Compton, AG, Hock DH, Walkiewicz, M, Brett, G, Pais, L, et al. medRxiv 2020.05.21.20104265

Type II Alexander disease caused by splicing erors and aberrant overexpression of an uncharacterized GFAP isoform. Helman G, Takanohashi, A, Hagemann, TL, Perng, MD, Walkiewicz, M, Woidill, S, et al. Hum Mutat. 2020;41:1131-1137.

Self-Organizing 3D Human Choroid Plexus-Ventricle-Cortical Organoids. Shaker MR, Cooper-White J, Wolvetang EJ. 2020:2020.09.30.321554.