Wikipedia

Steve Wilton

Stephen Donald Wilton AO, also known as Steve Wilton, is an Australian molecular biologist and academic, serving as the Foundation Professor of Molecular Therapy at Murdoch University and adjunct professor at the University of Western Australia (UWA).[1] He also fulfills dual roles as a Director at the Perron Institute for Neurological and Translational Science and deputy director at Murdoch's Centre for Molecular Medicine and Innovative Therapeutics (CMMIT).[2][3]

Stephen Donald Wilton
AO FAHMS
NationalityAustralian
Occupation(s)Molecular biologist and academic
AwardsWestern Australian Innovator of the Year Award, Western Australia Government (2012)
Officer Order of Australia, Department of the Prime Minister and Cabinet (2021)
Fellow Australian Academy of Health and Medical Sciences
Academic background
EducationBachelor of Science
Bachelor of Science Honours
Doctor of Philosophy
Alma materUniversity of Adelaide
Thesis (1984)
Academic work
InstitutionsThe Perron Institute for Neurological and Translational Science
The University of Western Australia
Murdoch University
Murdoch's Centre for Molecular Medicine and Innovative Therapeutics

Wilton and his colleague Sue Fletcher were among the first to explore the application of antisense oligomers for treating Duchenne muscular dystrophy (DMD). Their research led to the development of three exon-skipping compounds that have received approval from the US FDA for restoring functional dystrophin expression in the most common mutations associated with DMD.[4][5] His research in molecular therapy and translational medicine, emphasizing neuromuscular diseases like DMD, has earned him awards such as the Western Australian Innovator of the Year Award,[6] the Australian Museum Eureka Award for Translational Medicine,[7] and the LabGear Discovery Award. He was honored as an Officer of the Order of Australia for his contributions to medical research, neurological science, and muscular dystrophy.[8]

Wilton holds the title of Paul Harris Fellow at Rotary International[9] and is an Honorary Life Member of Muscular Dystrophy Western Australia and the Australasian Gene and Cell Therapy Society.[10]

Education

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Wilton obtained his Bachelor of Science degree from the University of Adelaide (AU) in 1978, followed by a Bachelor of Science with Honours in 1979. He served as Chief Production Biochemist at Geneworks in Adelaide,[11] from 1983 to 1987 after completing his Doctor of Philosophy degree, which was conferred in 1984 from AU.[12]

Career

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Wilton served as the Head of the DNA Sequencing Unit at the Australian Neuromuscular Research Institute from 1991 to 2004. He then directed the High Throughput Genotyping Facility at the Neurodegenerative Diseases Centre from 1999 to 2010 and occupied various roles at UWA until 2013, including Research Professor and Head of the Molecular Genetic Therapies Group.[13] In 2013, he assumed the position of Director at the Perron Institute and concurrently took on an appointment as Foundation Chair in Molecular Therapy at the Centre for Comparative Genomics at Murdoch University.[14] He was also involved in establishing Centre for Molecular Medicine and Innovative Therapeutics (CMMIT) as part of Murdoch's Health Futures initiative as a research joint venture with the Perron Institute in 2019.[15] He served as the Director of CMMIT until early 2023 and holds the position of Deputy Director[16] while serving on its Community Advisory Group and focusing on research on precision medicine and therapeutics for inherited and acquired disorders. Additionally, he holds positions as Foundation Chair and Co-Head of the Molecular Therapy Laboratory at Murdoch University,[17] and is an adjunct professor at UWA. He continues to be the Director at the Perron Institute for Neurological and Translational Science, a position he has held since 2013.[18]

Wilton has worked with various organizations, including Neuromuscular WA, MSWA, Rotary Club (Australia and International),[19] FSHD Global,[20] SMA Australia, and multiple Duchenne-focused groups.[21] He held the position of vice-president at the Australian Gene Therapy Society from 2007 to 2009 and served as President of the Australasian Gene and Cell Therapy Society (AGCTS),[22] while also holding a seat on the executive board of the World Muscle Society from 2010 to 2012. In addition, he co-founded RAGE Biotech and has remained an Ex Officio Committee member at AGCTS since 2013.[23]

Research

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Wilton's research spans molecular medicine, antisense nucleic acids, RNA splicing, and precision medicine, with applications for conditions including neurodegenerative diseases, cystic fibrosis, muscular dystrophies, multiple sclerosis, and respiratory conditions.[24][25] His research group has also developed pre-clinical candidates for adult-onset Pompe's disease, inflammation, and motor neuron disease. In collaboration with Monash University researchers, his group has focused on anti-inflammatory oligomers targeting Receptor for Advanced Glycation Endproducts (RAGE) for conditions such as sepsis, asthma, and emphysema.[26][27]

Wilton's work has been featured in media outlets including The West Australian,[28] Boston Business Journal,[21] Business News,[29] and ABC News.[30]

Molecular therapy and translational medicine

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Wilton's group was the first to report specific exon skipping in an animal model of Duchenne muscular dystrophy, which led ultimately to the development of a complete panel of splice-switching oligonucleotides.[31] Their work demonstrated the efficacy of phosphorodiamidate morpholino oligomers (PMOs) as splice-switching agents.[5] Their efforts culminated in the development of three drugs: Eteplirsen (Exondys 51), targeting exon 51 and approved in 2016; Golodirsen (Vyondys 53), targeting exon 53 and approved in 2019; and Casimersen (Amondys 45), approved in 2021.[32][33][34]

Wilton has demonstrated the broad applicability of splice-switching antisense oligomers in addressing various diseases such as Marfan syndrome[35] and juvenile-onset Parkinson's disease.[36] His earlier research identified rare dystrophin-positive fibers, termed revertant fibers, as a potential genetic therapy for DMD,[37] and proposed that inducing exon skipping in dystrophin pre-mRNA with antisense oligonucleotides (ASOs) could alleviate disease severity.[38] Additionally, he documented the first successful excision of dystrophin exon 23 in vitro using steric-blocking antisense oligomers[39] and demonstrated that weekly intravenous injections of morpholino antisense oligonucleotides (AONs) induce functional dystrophin expression in mdx mice, suggesting potential for DMD treatment.[40]

In 2006, Wilton developed antisense oligomers to induce exon skipping in the human dystrophin gene, showing varying efficiency across exons.[41] His research in 2009 showed the safe increase of dystrophin expression with intramuscular AVI-4658 administration, advancing DMD clinical trials,[42] while his 2011 work highlighted AVI-4658's well-tolerance, exon 51 skipping induction, and new dystrophin protein expression, indicating its potential as a disease-modifying drug for DMD.[43] Collaborating with R.N. Veedu and Fletcher, he stressed the importance of evaluating reported dystrophin expression and addressing drug safety, efficacy, and study parameters to promote targeted dystrophin exon removal.[44] Furthermore, he explored the potential of PMO in restoring functional expression of the SMN2 gene transcript in spinal muscular atrophy (SMA).[45]

Awards and honors

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  • 2009 – Paul Harris Fellow, Rotary International[9]
  • 2012 – Western Australian Innovator of the Year, Western Australian Department of Commerce[6]
  • 2013 – NSW Health Jamie Callachor Eureka Prize for Medical Research Translation, Australia Museum[7]
  • 2021 – Officer Order of Australia, Department of the Prime Minister and Cabinet[8]
  • 2022 – Industry Leadership Award, AusBiotech and Johnson & Johnson[32]
  • 2024 – Fellow of the Australian Academy of Health and Medical Sciences[46]

Selected articles

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  • Alter, J., Lou, F., Rabinowitz, A., Yin, H., Rosenfeld, J., Wilton, S. D., ... & Lu, Q. L. (2006). Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nature medicine, 12(2), 175–177.
  • Kinali, M., Arechavala-Gomeza, V., Feng, L., Cirak, S., Hunt, D., Adkin, C., ... & Muntoni, F. (2009). Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. The Lancet Neurology, 8(10), 918–928.
  • Cirak, S., Arechavala-Gomeza, V., Guglieri, M., Feng, L., Torelli, S., Anthony, K., ... & Muntoni, F. (2011). Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. The Lancet, 378(9791), 595–605.
  • Barrett, L. W., Fletcher, S., & Wilton, S. D. (2012). Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cellular and molecular life sciences, 69, 3613–3634.
  • Mejzini, R., Flynn, L. L., Pitout, I. L., Fletcher, S., Wilton, S. D., & Akkari, P. A. (2019). ALS genetics, mechanisms, and therapeutics: where are we now?. Frontiers in neuroscience, 13, 1310.

References

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  1. ^ "Steve Wilton". the UWA Profiles and Research Repository.
  2. ^ "Company".
  3. ^ "Our people - Perron Institute". www.perroninstitute.org. October 26, 2021.
  4. ^ "Rewriting the rules for rare diseases". www.murdoch.edu.au.
  5. ^ a b "Molecular Therapies - Perron Institute". www.perroninstitute.org.
  6. ^ a b "Breakthrough for boys who can't walk shortlisted for WA Innovation Award : Archive Page : The University of Western Australia". www.news.uwa.edu.au.
  7. ^ a b "2013 Australian Museum Eureka Prizes winners". The Australian Museum.
  8. ^ a b "Praise for life's work fighting muscular dystrophy". The West Australian. June 13, 2021.
  9. ^ a b "Club History | Rotary Club of West Perth".
  10. ^ "Presidents Message – AGCTS".
  11. ^ "The Case of Bresagen" (PDF).
  12. ^ "Perron Institute Director Steve Wilton WA of the Year award finalist". www.perroninstitute.org. May 14, 2016.
  13. ^ "Worldwide patent opens doors to treatment of muscular dystrophy : Archive Page : The University of Western Australia". www.news.uwa.edu.au.
  14. ^ "Steve Wilton". Business News.
  15. ^ "Working together to solve global health challenges through the precision medicine revolution" (PDF).
  16. ^ "Professor Steve Wilton" (PDF).
  17. ^ "Professor Steve Wilton AO - Perron Institute". www.perroninstitute.org.
  18. ^ "Genetic researcher shares insights on TEDxPerth". www.murdoch.edu.au.
  19. ^ "Club Services | The Rotary Club of Masterton South".
  20. ^ Global, FSHD. "The History of FSHD".
  21. ^ a b "The 20-year road to make the world's first exon-skipping drug".
  22. ^ "AGTS Newsletter August Issue 2014" (PDF).
  23. ^ "AGCTS Exec Committee – AGCTS".
  24. ^ "Steve Wilton". scholar.google.com.
  25. ^ Santos, Isaura (November 7, 2014). "Almost $800,000 To Develop Genetic Drugs For DMD, Other Rare Diseases Awarded To Murdoch University". musculardystrophynews.com.
  26. ^ "RAGE Biotech".
  27. ^ "RAGE Biotech - Medicine, Nursing and Health Sciences".
  28. ^ "Meet Billy — the 16yo walking, talking miracle". The West Australian. April 29, 2017.
  29. ^ "Perron Institute partners in Asia". 28 November 2017.
  30. ^ "Duchenne muscular dystrophy drug developed by Perth researchers approved by FDA". ABC News. September 20, 2016 – via www.abc.net.au.
  31. ^ "Pioneering treatments for Duchenne muscular dystrophy". Research - Health Futures Institute.
  32. ^ a b "WA scientists recognised for life changing hat trick". www.murdoch.edu.au.
  33. ^ "Medical breakthrough wins Eureka Prize". www.murdoch.edu.au.
  34. ^ Gurunathan, Sujatha (November 17, 2020). "Once a Wild Idea, Successful First-Generation Exon-Skipping Therapies Pave the Way for Personalized Treatments".
  35. ^ Cale, Jessica M.; Greer, Kane; Fletcher, Sue; Wilton, Steve D. (January 3, 2021). "Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52". International Journal of Molecular Sciences. 22 (7): 3479. doi:10.3390/ijms22073479. PMC 8037683.
  36. ^ Li, Dunhui; Aung-Htut, May T.; Ham, Kristin A.; Fletcher, Sue; Wilton, Steve D. (January 3, 2020). "A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson's Disease Arising from Parkin Mutations". International Journal of Molecular Sciences. 21 (19): 7282. doi:10.3390/ijms21197282. PMC 7582384. PMID 33019779.
  37. ^ "Redirecting". linkinghub.elsevier.com.
  38. ^ "Redirecting". linkinghub.elsevier.com.
  39. ^ Lu, Qi Long; Mann, Christopher J.; Lou, Fang; Bou-Gharios, George; Morris, Glenn E.; Xue, Shao-an; Fletcher, Sue; Partridge, Terence A.; Wilton, Stephen D. (August 3, 2003). "Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse". Nature Medicine. 9 (8): 1009–1014. doi:10.1038/nm897 – via www.nature.com.
  40. ^ Alter, Julia; Lou, Fang; Rabinowitz, Adam; Yin, HaiFang; Rosenfeld, Jeffrey; Wilton, Steve D.; Partridge, Terence A.; Lu, Qi Long (February 3, 2006). "Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology". Nature Medicine. 12 (2): 175–177. doi:10.1038/nm1345. PMID 16444267 – via www.nature.com.
  41. ^ "Antisense Oligonucleotide-induced Exon Skipping Across the Human Dystrophin Gene Transcript - ScienceDirect".
  42. ^ "Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study - The Lancet Neurology".
  43. ^ "Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study - The Lancet".
  44. ^ "Redirecting". linkinghub.elsevier.com.
  45. ^ "A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse".
  46. ^ "Professor Steve Wilton". Australian Academy of Health and Medical Sciences. 2024-10-24. Retrieved 2024-10-25.
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