Medicine & Health School of Biomedical Sciences

Froehlich Group: CNS Gene Therapy Lab

Translational Neuroscience Facility
2024-10-Dominik-Froehlich-group

The CNS Gene Therapy Group investigates the molecular mechanisms that govern normal and pathological functions of neurons and myelin-forming cells in the central nervous system. Our primary focus is on a group of devastating childhood brain disorders known as leukodystrophies. The term derives from the Greek words leuko (white), dys (abnormal), and troph (growth), reflecting the abnormal development of brain white matter. Leukodystrophies are rare genetic diseases, affecting approximately 1 in 4,600 live births, and are associated with early onset, severe neurological decline, and high childhood mortality. To date, no effective treatments exist.

Our mission is to develop targeted gene therapy strategies for leukodystrophies and other neurological disorders. A crucial first step is the creation of accurate pre-clinical disease models, which allow us to study disease mechanisms in detail and test innovative therapies. Building on these models, we leverage cutting-edge adeno-associated virus (AAV) platforms to deliver therapeutic genes to the CNS.

We are advancing AAV technologies in two key directions:

  • Achieving widespread, stable, and safe gene expression across the CNS following intracranial or systemic delivery
  • Retargeting AAV vectors to overcome inherent neurotropism and selectively target specific CNS cell types, including glial cells

Our group employs state-of-the-art techniques — ranging from behavioural testing, neurogenetics, and molecular biology to advanced histology and neuroimaging — to characterise disease models and rigorously assess the outcomes of gene therapy.

Since 2023, the CNS Gene Therapy Group has been supported by new research grants from the NHMRC and MRFF. This funding enables us to expand beyond leukodystrophies to include dementias such as globular glial tauopathies and inherited neurological disorders like hereditary spastic paraplegias (HSPs). By refining our pre-clinical models and gene therapy platforms, we aim to uncover the underlying disease mechanisms and establish replicable therapeutic frameworks for currently untreatable neurological conditions.

Current projects

  • Cure Leukodystrophy: Developing pre-clinical models and gene therapy strategies with the goal of establishing a framework for treating white matter diseases
  • Globular Glial Tauopathies: Investigating oligodendroglial dysfunction to uncover mechanisms of neurodegeneration and identify therapeutic opportunities
  • Hereditary Spastic Paraplegia (SPG-56): Establishing a novel gene therapy for SPG-56 and creating a framework for treating other forms of HSP
  • Peripheral Nerve Repair: Using Bionic array-Directed Gene Electrotransfer (BaDGE®) to deliver mRNA/DNA-encoded neurotrophins that promote nerve regeneration and muscle reinnervation

Highlighted publications

  1. Kalotay E, Klugmann M, Housley GD and Fröhlich D (2023) Recessive aminoacyl-tRNA synthetase disorders: Lessons learned from in vivo disease models. Frontiers in Neuroscience 17:1182874.
  2. Kalotay E, Klugmann M, Housley GD and Fröhlich D (2023) Dominant aminoacyl-tRNA synthetase disorders: Lessons learned from in vivo disease models. Frontiers in Neuroscience 17:1182845.
  3. Klugmann M, Suchowerska AK, Housley GD, Fröhlich D (2023) Histological and biochemical methods to assess aminoacyl-tRNA synthetase expression in human post-mortem brain tissue. Rare Disease and Orphan Drugs Journal 2:8.
  4. Fröhlich D, Kalotay E, von Jonquieres G, Bongers A, Lee B, Suchowerska AK, Housley GD and Klugmann M (2022) Dual-function AAV gene therapy reverses late-stage Canavan disease pathology in mice. Frontiers in Molecular Neuroscience 15: 1061257.
  5. Klugmann M, Kalotay E, Delerue F, Ittner LM, Bongers A, Yu J, Morris MJ, Housley GD and Fröhlich D (2022) Developmental delay and late onset HBSL pathology in hypomorphic Dars1M256L mice. Neurochemical Research 47(7): p. 1972-1984.
  6. Fröhlich D, Gessler DJ and Klugmann M (2022) Editorial: Myelin Repair: At the Crossing-Lines of Myelin Biology and Gene Therapy. Frontiers in Cellular Neuroscience 16:853742.
  7. Muthiah A, Housley GD, Klugmann M and Fröhlich D (2021) The Leukodystrophies HBSL and LBSL—Correlates and Distinctions. Frontiers in Cellular Neuroscience 14:626610.
  8. Fröhlich D, Mendes MI, Kueh AJ, Bongers A, Herold MJ, Salomons GS, Housley GD and Klugmann M (2021) A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL. Frontiers in Cellular Neuroscience 14:625879.
  9. Frühbeis C, Kuo-Elsner WP, Müller C, Barth K, Peris L, Tenzer S, Möbius W, Werner HB, Nave KA, Fröhlich D and Krämer-Albers EM (2020) Oligodendrocytes support axonal transport and maintenance via exosome secretion. PLoS Biology 18(12): e3000621.
  10. Das A, Fröhlich D, Achanta LB, Rowlands BD, Housley GD, Klugmann M and Rae CD (2020) L-Aspartate, L-ornithine and L-ornithine-L-aspartate (LOLA) and their impact on brain energy metabolism. Neurochemical Research 45(6): 1438-1450.
  11. Auber M, Fröhlich D, Drechsel O, Karaulanov E and Krämer-Albers EM (2019) Serum-free media supplements carry miRNAs that co-purify with extracellular vesicles. Journal of Extracellular Vesicles 8(1): 1656042.
  12. Fröhlich D, Suchowerska AK, Voss C, He R, Wolvetang E, von Jonquieres G, Simons C, Fath T, Housley GD and Klugmann M (2018) Expression Pattern of the Aspartyl-tRNA Synthetase DARS in the Human Brain. Frontiers in Molecular Neuroscience 11: 81.
  13. von Jonquieres G, Spencer ZHT, Rowlands BD, Klugmann CB, Bongers A, Harasta AE, Parley KE, Cederholm J, Teahan O, Pickford R, Delerue F, Ittner LM, Fröhlich D, McLean CA, Don AS, Schneider M, Housley GD, Rae CD and Klugmann M (2018) Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy. Acta Neuropathologica 135(1): 95-113.
  14. Fröhlich D, Suchowerska AK, Spencer ZH, von Jonquieres G, Klugmann CB, Bongers A, Delerue F, Stefen H, Ittner LM, Fath T, Housley GD, Klugmann M (2017) In vivo characterization of the aspartyl-tRNA synthetase DARS: Homing in on the leukodystrophy HBSL. Neurobiology of Disease 97(Pt A): 24-35.
  15. von Jonquieres G, Fröhlich D, Klugmann CB, Wen X, Harasta AE, Ramkumar R, Spencer ZH, Housley GD, Klugmann M (2016) Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes. Frontiers in Molecular Neuroscience 9: 13.

 

Our experts

Group Leader, Dominik Froehlich
Dominik Froehlich
Group Leader,
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Team members

  • Matthias Klugmann – Co-lead
  • Elizabeth Kalotay – PhD candidate / Research assistant
  • Elena Venuti – PhD candidate
  • Sreya Santhakumar – Research assistant
  • Connor Karozis – PhD candidate

Honor Students

  • Kwannatee Morey-Hype (Neuroscience Honours)
  • Richa Chaluvadi (Medicine Honours)

Collaborators

  • Lars Ittner and Fabien Delerue, Macquarie University, Australia
  • Ernst Wolvetang, University of Queensland, Australia
  • Caroline Rae, Neuoscience Research Australia (NeuRA), Australia
  • Richard Leventer and Chloe Stutterd, Murdoch Children’s Research Institute (MCRI), Australia
  • Leszek Lisowski, Children’s Medical Research Institute (CMRI), Australia
  • Shelley Forrest and Gabor Kovacs, University of Toronto, Canada
  • Eva-Maria Krämer-Albers, University of Mainz, Germany
  • Gajja Salomons and Marisa Mendes, Amsterdam UMC, Netherlands
  • Marjo van der Knaap and Javier Triñanes Ramos, Amsterdam UMC, Netherlands
  • Chelsea Goulton and Jay Bertran-Gonzalez, UNSW Sydney, Australia
  • Kate Michie, UNSW Sydney, Australia
  • Andre Bongers, UNSW Sydney, Australia

Grants & funding

  • European Leukodystrophy Association (ELA) Project Grant (2025 - 2027); Establishing efficacy and safety of HBSL gene therapy in preclinical disease models ($325,000)
  • Medical Research Future Fund (MRFF) Stem Cell Therapies Mission (2023 -2025); Moon's Mission: creating a replicable therapeutic framework for hereditary spastic paraplegias ($940,424)
  • National Health and Medical Research Council (NHMRC) Ideas Grant (2023 - 2026); Understanding neurodegeneration caused by oligodendroglial dysfunction ($1,025,253)
  • National Health and Medical Research Council (NHMRC) Ideas Grant (2021 - 2026); Bionic-array Directed Gene Electrotransfer for Treating Focal Brain Disorders ($1,941,000)
  • Medical Research Future Fund (MRFF) Accelerated Research (2019 -2023); Massimo’s Mission – The Leukodystrophy Flagship ($3,000,000)
  • European Leukodystrophy Association (ELA)project grant (2019 -2022); Towards preclinical proof-of-concept for HBSL gene therapy ($316,000)
  • European Leukodystrophy Association (ELA) pilot grant (2016); Modelling and treatment of the novel leukoencephalopathy HBSL ($69,000)
Research Theme

Neuroscience |