Development of a targeted BioPROTAC degrader selective for misfolded SOD1

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. Cashman, Darren N. Saunders, Luke McAlary, Jeremy S. Lum () and Justin J. Yerbury
Additional contact information
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
Lars M. Ittner: Macquarie University
Kara L. Vine-Perrow: University of Wollongong
Heath Ecroyd: University of Wollongong
Neil R. Cashman: University of British Columbia
Darren N. Saunders: University of Sydney
Luke McAlary: University of Wollongong
Jeremy S. Lum: University of Wollongong
Justin J. Yerbury: University of Wollongong

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65481-w

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