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Development of a targeted BioPROTAC degrader selective for misfolded SOD1

Author

Listed:
  • Christen G. Chisholm

    (University of Wollongong)

  • Rachael Bartlett

    (University of Wollongong)

  • Mikayla L. Brown

    (University of Wollongong)

  • Emma-Jayne Proctor

    (University of Wollongong)

  • Natalie E. Farrawell

    (University of Wollongong)

  • Jody Gorman

    (University of Wollongong)

  • Fabien Delerue

    (Macquarie University
    The University of Texas MD Anderson Cancer Centre)

  • Lars M. Ittner

    (Macquarie University
    Celosia Therapeutics)

  • Kara L. Vine-Perrow

    (University of Wollongong)

  • Heath Ecroyd

    (University of Wollongong)

  • Neil R. Cashman

    (University of British Columbia
    ProMIS Neurosciences)

  • Darren N. Saunders

    (University of Sydney)

  • Luke McAlary

    (University of Wollongong)

  • Jeremy S. Lum

    (University of Wollongong)

  • Justin J. Yerbury

    (University of Wollongong)

Abstract

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we demonstrate that the presence of the BioPROTAC delays disease progression in the SOD1G93A mouse model of ALS. Delayed disease progression is associated with protection of motor neurons, a reduction of insoluble SOD1 accumulation and preservation of innervated neuromuscular junctions. These findings provide proof-of-concept evidence and a platform for developing BioPROTACs as a therapeutic strategy for the targeted degradation of neurotoxic misfolded species in the context of neurodegenerative diseases.

Suggested Citation

  • Christen G. Chisholm & Rachael Bartlett & Mikayla L. Brown & Emma-Jayne Proctor & Natalie E. Farrawell & Jody Gorman & Fabien Delerue & Lars M. Ittner & Kara L. Vine-Perrow & Heath Ecroyd & Neil R. Ca, 2025. "Development of a targeted BioPROTAC degrader selective for misfolded SOD1," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65481-w
    DOI: 10.1038/s41467-025-65481-w
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    References listed on IDEAS

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    1. Joseph L. Watson & David Juergens & Nathaniel R. Bennett & Brian L. Trippe & Jason Yim & Helen E. Eisenach & Woody Ahern & Andrew J. Borst & Robert J. Ragotte & Lukas F. Milles & Basile I. M. Wicky & , 2023. "De novo design of protein structure and function with RFdiffusion," Nature, Nature, vol. 620(7976), pages 1089-1100, August.
    2. Oliver Hsia & Matthias Hinterndorfer & Angus D. Cowan & Kentaro Iso & Tasuku Ishida & Ramasubramanian Sundaramoorthy & Mark A. Nakasone & Hana Imrichova & Caroline Schätz & Andrea Rukavina & Koraljka , 2024. "Targeted protein degradation via intramolecular bivalent glues," Nature, Nature, vol. 627(8002), pages 204-211, March.
    3. Alexander Chan & Rebecca M. Haley & Mohd Altaf Najar & David Gonzalez-Martinez & Lukasz J. Bugaj & George M. Burslem & Michael J. Mitchell & Andrew Tsourkas, 2024. "Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
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