Medicine & Health School of Biomedical Sciences

Froehlich Lab: Nervous System Gene Therapy and Repair Group

Translational Neuroscience Facility
Nervous System Gene Therapy and Repair Group (Dr. Dominik Froehlich)

The Nervous System Gene Therapy and Repair Group investigates the molecular mechanisms that govern normal and pathological functions of neurons and myelin-forming cells across both the central and peripheral nervous systems. Our research spans neurodevelopmental, neurodegenerative, and injury-related conditions, with the goal of developing transformative gene-based therapies that not only treat disease but also promote neural repair and regeneration.

A major focus of the group is on leukodystrophies — a class of rare genetic disorders characterised by abnormal development of brain white matter (from the Greek leuko = white, dys = abnormal, troph = growth). Affecting approximately 1 in 4,600 live births, these devastating childhood diseases are associated with early onset, severe neurological decline, and high mortality, and currently lack effective treatments.

Our mission is to develop targeted gene therapy strategies for disorders of both the central and peripheral nervous systems. We combine the development of accurate pre-clinical models with advanced gene delivery technologies to better understand disease mechanisms and to design innovative therapeutic approaches.

In addition to CNS-directed therapies, we are pioneering gene-based strategies to promote repair following peripheral nerve injury. Using the Bionic array-Directed Gene Electrotransfer (BaDGE®) platform, developed at the UNSW Translational Neuroscience Facility, we deliver RNA- and DNA-encoded neurotrophins directly to injured nerves to enhance regeneration and enable targeted muscle reinnervation.

Our work integrates multiple gene delivery platforms, including adeno-associated virus (AAV) vectors and next-generation electrotransfer technologies. We are advancing these approaches in several key directions: 

  • Achieving widespread, stable, and safe gene expression within the nervous system 
  • Retargeting AAV vectors to selectively transduce specific cell types, including glial cells
  • Developing localised, device-enabled gene delivery strategies for nerve repair and regeneration

To support these efforts, we employ state-of-the-art methodologies spanning behavioural neuroscience, neurogenetics, molecular biology, advanced histology, and neuroimaging to rigorously characterise disease models and evaluate therapeutic outcomes.

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
  • Lily Pearson –  Post-Doctoral Fellow
  • Sreya Santhakumar – Research assistant
  • Elizabeth Kalotay – PhD candidate / Research assistant
  • Elena Venuti – PhD candidate
  • Connor Karozis – PhD candidate

Honor Students

  • Luke Livolsi (SBMS Honours)
  • 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

  • National Health and Medical Research Council (NHMRC) Ideas Grant (2026 - 2028); Neuromuscular BaDGE - Electrotransfer of Naked Neurotrophin Gene-based Therapeutics for Accelerated Nerve Regeneration and Muscle Reinnervation ($1,722,656)
  • 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 |