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Genetic Therapies – Molecular Therapies, Nucleic Acid Therapeutics and Motor Neurone Disease Therapeutics Research.

Molecular Therapies Research

The Perron Institute’s Molecular Genetic Therapies Research led by Professors Steve Wilton and Sue Fletcher has a long history of cutting-edge research on novel genetic therapies for neuromuscular disorders, particularly Duchenne muscular dystrophy. In September 2016, the USA Food and Drug Administration (FDA) gave accelerated approval to a new treatment for Duchenne created by Professor Steve Wilton, Professor Sue Fletcher and their team. Exondys-51 (previously Eteplirsen) is the first dystrophin restoring drug of its type ever approved by the FDA.

Research Focus

The main focus of the Genetic Therapies Research is the use of small genetic ‘patches’ called antisense oligonucleotides (AOs) to mask part of a genetic message associated with a particular inherited disease. In the case of Duchenne muscular dystrophy (DMD), the defective genetic message is associated with the gene for the protein dystrophin, which plays a pivotal role in maintaining muscle structure and integrity.

Research Areas

  • Molecular genetics
  • Antisense oligonucleotide technologies
  • Genetic therapies
  • Exon skipping
  • Splice switching
  • Muscle repair and regeneration
  • Inherited neuromuscular diseases
  • Duchenne muscular dystrophy
  • Spinal muscular atrophy

Head of Research

Members

Professor Steve Wilton, the Perron Institute Scientific Director, Foundation Chair Molecular Therapy

Professor Sue Fletcher, the Perron Institute Director of Research, Deputy Director MTL

Abbie Adams, Senior Research Officer

Dr May Aung-Htut, Post Doctoral Scientist

Julie Gilmore, PhD Student

Kane Greer, Research Officer

Russell Johnson, Senior Research Officer (Histology)

Niall Keegan, Masters Student

Ianthe Pitout, PhD Student

Loren Price, PhD Student

Kristin West, Research Officer

Jodie Williamson, PA/Projects Officer

Achievements

AWARDS

  • 2014 LabGear Australia Discovery Science Award (S Wilton)
  • 2013 Eureka Prize for Medical Research Translation (S Wilton and S Fletcher)
  • 2012 Western Australian Innovator of the Year Award (S Wilton and S Fletcher)

GRANTS

Targeted alternative splicing: a common therapeutic platform to treat inherited diseases

Wilton, Fletcher, Zheng, Mastaglia

2018-2020 $798,165. NHMRC   Application 1144791

Stargardt disease

Chen, de Roach, Hunt and Wilton

2018-2019 $120,000. Macular Disease Foundation.

Sarepta Therapeutics Contract Research

Correlation study: PMO relative activity ranking in DMD patient myoblasts and normal myoblasts
US$1,405,350

NHMRC European Union

RD-CONNECT: An integrated platform connecting registries, biobanks and clinical bioinformatics for rare disease research
$989,884

MDA USA

Oligomer design & validation for DMD: quantum improvements in exon skipping
US$300,000

NHMRC

Optimization of splice switching therapies to treat Duchenne muscular dystrophy”. Bellgard MI, Wilton SD, Fletcher S.
$439,000

NHMRC

The L-type calcium as a reporter of successful morpholino oligomer therapy in treatment of Duchenne muscular dystrophy cardiomyopathy”. Hool L, Fletcher S, Wilton SD.
$575,558

PUBLICATIONS

2018

Flynn LL, Mitrpant C, Pitout IL, Fletcher S, and Wilton SD, Antisense oligonucleotide mediated terminal intron retention of the SMN2 transcript. Mol Ther Nucleic Acids, 2018. (in press).

Martinovich KM, Shaw NC, Kicic A, Schultz A, Fletcher S, Wilton SD, and Stick SM, The potential of antisense oligonucleotide therapies for inherited childhood lung diseases. Mol Cell Pediatr, 2018. 5(1): p. 3.

2017

Review: Inherited retinal disease therapy targeting precursor messenger ribonucleic acid. Di Huang, Sue Fletcher, Samuel McLenachan, David A Mackey, Norman Palmer, Steve D Wilton, Fred Chen. Vision doi:10.3390/vision1030022.

Polyglutamine ataxias: From clinical and molecular features to current therapeutic strategies. Craig S. McIntosh, May Thandar Aung-Htut, Sue Fletcher and Steve D. Wilton. Genetic Syndromes and Gene Therapy DOI: 10.4172/2157-7412.1000319.

Inherited retinal disease therapy targeting precursor messenger ribonucleic acid

Huang D, Fletcher S, Wilton SD, McLenachan S, Mackey DA, Chen FK

Vision (2017) in press

 

Efficient Skipping of Single Exon Duplications in DMD Patient-Derived Cell Lines Using an Antisense Oligonucleotide Approach

Wein N, Vulin A, Findlay AR, Gumienny F, Huang N, Wilton SD, Flanigan KM

2017 Journal Neuromuscul Dis 4: 199-207

 

Restoration of Cftr Function by Antisense Oligonucleotide Splicing Modulation

Oren Y, Tur-Sinai MI, Ozeri-Galai E, Avizur O, Mutyam V, Wilton SD, Rowe SM, Kerem B

2017 Pediatric Pulmonology 52: S313-S313

 

Response to “Railroading at the FDA”

Muntoni F, Fletcher S and Wilton SD

2017 Nat Biotechnol 35: 207-209

 

Corrigendum: Response to “Railroading at the FDA”

Muntoni F, Fletcher S, Wilton SD

2017 Nat Biotechnol 35: 481

 

Functional improvement of dystrophic muscle by repression of utrophin: let-7c interaction

Mishra MK, Loro E, Sengupta K, Wilton SD, Khurana TS

2017 PLoS One 12: e0182676

 

Translational development of splice-modifying antisense oligomers

Fletcher S, Bellgard MI, Price L, Akkari AP, Wilton SD

2017 Expert Opin Biol Ther 17: 15-30

 

A Dominant-Negative COL6A1 Pseudoexon Insertion Is Skippable Using Splice-Modulating Oligonucleotides

Bolduc V, Foley AR, Donkervoort S, Hu Y, Cummings BB, Lek M, Sarathy A, Sizov K, Degefa HS, Wagener R, Hennig GW, Hanssen E, Lamande SR, Muntoni F, Wilton SD, Macarthur DG, Bonnemann CG

2017 Molecular Therapy 25: 119-120

 

A common dominant-negative COL6A1 pseudo-exon insertion is skippable using splice-modulating oligonucleotides

Bolduc V, Foley A, Donkervoort S, Hu Y, Cummings B, Lek M, Sarathy A, Sizov K, Degefa H, Wagener R, Hennig G, Hanssen E, Lamande S, Muntoni F, Wilton SD, Macarthur DG, Bonnemann C

2017 Neuromuscular Disorders 27: S177-S177

 

Comprehending the Health Informatics Spectrum: Grappling with System Entropy and Advancing Quality Clinical Research

Bellgard MI, Chartres N, Watts GF, Wilton SD, Fletcher S, Hunter A, Snelling T

2017 Front Public Health 5: 224

Rational Design of Short Locked Nucleic Acid-Modified 2′-O-Methyl Antisense Oligonucleotides for Efficient Exon-Skipping In Vitro

Le BT, Adams AM, Fletcher S, Wilton SD and Veedu RN

2017 Mol Ther Nucleic Acids 9: 155-161

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh CS, Aung-Htut MT, Fletcher S, Wilton SD

Journal of Genetic Syndromes and Gene Therapies 8: 319. doi: 10.4172/2157-7412.1000319

2016

Toh, Z.Y.C., Aung-Htut, M.T., Pinniger, G., Adams, A.M., Krishnaswarmy, S., Wong, B.L., Fletcher, S., Wilton, S.D. 2016, ‘Deletion of dystrophin in-frame exon 5 leads to a severe phenotype: Guidance for exon skipping strategies’, PLoS ONE, 11, 1, pp. 1-17.

Part 2: Making the “unproven” “proven”

Weiss DJ, Rasko JE, Cuende N, Ruiz MA, Ho HN, Nordon R, Wilton S, Dominici M and Srivastava A

Cytotherapy 18: 120-123

Correcting the NLRP3 inflammasome deficiency in macrophages from autoimmune NZB mice with exon skipping antisense oligonucleotides

Thygesen SJ, Sester DP, Cridland SO, Wilton SD and Stacey KJ

Immunol Cell Biol 94: 520-524

Antisense oligonucleotide development for the treatment of muscular dystrophies

Le BT, Veedu RN, Fletcher S, Wilton SD

Expert Opin Orph Drugs 4(2): 139-152

Book Chapters

Aptamers: Tools for Targeted Nanotherapy and Molecular Imaging, ed. RN Veedu, In: Aaldering LJ, Krishnan S, Fletcher S, Wilton S, Veedu RN*,

Pan Stanford Publishing, Singapore, 2016, pp. 151-167

2015

  • Aaldering, L.J., Tayeb, H., Krishnan, S., Fletcher, S., Wilton, S.D. & Veedu, R.N. (2015) Smart functional nucleic acid chimeras: Enabling tissue specific RNA targeting therapy 
RNA Biology 12 (4), pp. 412-425
  • Wein, N., Vulin, A., Falzarano, M.S., Szigyarto, C.A.-K., Maiti, B., Findlay, A., Heller, K.N., Uhlén, M., Bakthavachalu, B., Messina, S., Vita, G., Passarelli, C., Brioschi, S., Bovolenta, M., Neri, M., Gualandi, F., Wilton, S.D., Rodino-Klapac, L.R., Yang, L., Dunn, D.M., Schoenberg, D.R., Weiss, R.B., Howard, M.T., Ferlini, A. & Flanigan, K.M. (2015) Erratum: Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice: (Nature Medicine (2014) 20 (992-1000) DOI:10.1038/nm.3628) Nature Medicine 21 (5), pp. 537
  • Wein, N., Vulin, A., Falzarano, M.S., Szigyarto, C.A.-K., Maiti, B., Findlay, A., Heller, K.N., Uhlén, M., Bakthavachalu, B., Messina, S., Vita, G., Passarelli, C., Brioschi, S., Bovolenta, M., Neri, M., Gualandi, F., Wilton, S.D., Rodino-Klapac, L.R., Yang, L., Dunn, D.M., Schoenberg, D.R., Weiss, R.B., Howard, M.T., Ferlini, A. & Flanigan, K.M. (2015). Corrigendum: Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice (Nature Medicine (2014) Nature Medicine 21 (4), pp. 414
  • Wilton, S.D., Veedu, R.N. & Fletcher, S. (2015) The emperor’s new dystrophin: Finding sense in the noise. Trends in Molecular Medicine – in press
  • Roy., K., Kanwar, R.K., Antonio Cheung, C.H., Fleming, C.L., Veedu,R.N., Krishnakumar. S. & Kanwar. J.R. (2015) Locked nucleic acid modified bi-specific aptamer- targeted nanoparticles carrying survivin antagonist towards effective colon cancer therapy Royal Society of Chemistry Advances (RSC Advances) 29008-29016
  • Edwards, S.L., Poongavanam, V., Kanwar, J.R., Roy, K., Hillman, K.M., Prasad, N., Leth-Larsen, R., Petersen, M., Marušič, M., Plavec, J., Wengel, J. & Veedu, R.N. (2015) Targeting VEGF with LNA-stabilized G-rich oligonucleotide for efficient breast cancer inhibition Chemical Communications 51 (46), pp 9499-9502
  • Greer, K., Kayla, M., Rice, E., Kuster, L., Barrero, R.A., MaBellgard. M.I., Lynch, B.J., Foley, A.R., Rathallaigh, E.O., Wilton, S.D. & Fletcher, F. (2015) Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient. Molecular Genetics and Genomic Medicine doi: 10.1002/mgg3.144.
  • Barrett LW, Fletcher S, Barrero RA, Bellgard MI, Flanigan KM, Wong B, Wilton SD. (2014). Targeted Suppression of a Dystrophin Pseudo-exon using Antisense Oligonucleotides. Genetic Syndromes & Gene Therapy. 2014; 5.
  • Bellgard MI, Sleeman MW, Guerrero FD, Fletcher S, Baynam G, Goldblatt J, Rubinstein Y, Bell C, Croft S, Barrero R, Bittles AH, Wilton SD, Mason CE and Weeramanthri T. (2014). Rare Disease Research Roadmap: Navigating the bioinformatics and translational challenges for improved patient health outcomes in Health Policy and Technology.
  • Greer KL, Lochmuller H, Flanigan K, Fletcher S, Wilton SD. (2014). Targeted exon skipping to correct exon duplications in the dystrophin gene. Molecular therapy Nucleic acids 2014; 3:e155.
  • Luo YB, Mastaglia FL, Wilton SD.  (2014). Normal and aberrant splicing of LMNA.  J Medical Genetics 2014; 51(4): 215-223.
  • Luo YB, Mitrpant C, Adams AM, Johnsen RD, Fletcher S, Mastaglia FL, Wilton SD.  (2014). Antisense oligonucleotide induction of progerin in human myogenic cells.  PLoS ONE. 2014; 9(6):e98306.
  • Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlen M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Gualandi F, Wilton SD, Rodino-Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM. (2014). Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nature Medicine 2014; 20:992-1000.
  • Wein N, Vulin A, Falzanaro MS, Szigyarto CaK, Maiti B, Findlay A, Heller KN, Uhlen M, Bakthavachalu B, Messina S, Vita GL, Gualandi F, Wilton SD, Yang L, Dunn DM, Schoenberg D, Weiss RB, Howard MT, Ferlini A and Flanigan KM. (2014). Successful Use of Out-of-Frame Exon 2 Skipping Induces IRES-Driven Expression of the N-Truncated Dystrophin Isoform: Promising Approach for Treating Other 5 ‘ Dystrophin Mutations. Molecular Therapy 22: S294-S295.
  • Wilton SD, Fletcher S, Flanigan KM. (2014). Dystrophin as a therapeutic biomarker: are we ignoring data from the past? Neuromuscul Disord. 2014; 24:463-466

More Information

DUCHENNE MUSCULAR DYSTROPHY (DMD)

DMD, the most common form of muscular dystrophy, is a relentlessly progressive and devastating genetic disorder that causes loss of muscle function leading to paralysis, loss of ambulation and premature death. The disorder primarily affects boys because the defective gene is located on the X-chromosome. DMD affects about 20,000 babies born every year worldwide. The disease knows no boundaries, touching all races and cultures. As the disease progresses, muscle wasting occurs with muscle tissue being replaced by fat and fibrotic tissue. By the age of 10, braces are commonly required to aid in walking and most patients become wheelchair-bound by the age of 12.

There is currently no cure for DMD but over the last two decades, progress has been achieved in mitigating the symptoms of the disease through the use of steroids and better respiratory care.

DMD CLINICAL TRIAL

The Group has used AOs through a process termed ‘splice switching’ to alter expression of the dystrophin gene so that a shortened but still functional form of the protein is produced. The approach is groundbreaking. One AO, eteplirsen, which targets the defect found in the most common sub-type of DMD, is now in Phase 2 clinical trial in the United States. The results of this trial – now in its third year – continue to be highly encouraging. Eteplirsen, which has been established to be safe and well tolerated with no major adverse effects – as predicted from Professors Wilton and Fletcher’s preclinical studies – alters dystrophin gene expression leading to the appearance of dystrophin protein in muscle. Most importantly, eteplirsen dramatically affects walking ability, treated boys showing only a marginal decline in walking ability even after 2 years. This contrasts with the catastrophic decline in walking ability normally seen in DMD boys of this age.

The results of the clinical trial are unprecedented and for the first time ever offer hope that an effective treatment for DMD may be on the horizon that reduces the decline in functionality and mobility in DMD patients and extends life expectancy. Of the trial’s outcomes, Dr. Jerry Mendell, Director of the Centers for Gene Therapy and Muscular Dystrophy at the Nationwide Children’s Hospital (Columbus, Ohio) said:

“These data represent a significant milestone and a defining moment of progress and hope for patients with DMD and their families, as well as for those of us in the scientific community who have been pursuing potential treatments for this devastating and deadly disease for decades.”

Professor Wilton and Fletcher’s research continues to receive worldwide recognition. They were recipients of the Western Australian Innovator of the Year Award in 2012 and, more recently, received the 2013 Eureka Prize for Medical Research Translation – one of the ‘Oscars’ of Australian science.

RESEARCH TRANSLATION FOR OTHER CONDITIONS

The concept underlying the use of AOs has broad applicability to a range of genetic conditions. 
It is estimated that about 10-15% of all inherited diseases are caused by gene mutations theoretically amenable to AO treatment, including conditions such as:

  • Alzheimer’s
  • Congenital muscular dystrophy
  • Cystic fibrosis
  • Epilepsy
  • Motor neurone disease
  • Multiple sclerosis
  • Pompe’s disease
  • Spinal muscular atrophy (SMA)

Potential applications are potentially limitless.

SPINAL MUSCULAR ATROPHY

One example of this is the use of AOs in the treatment of spinal muscular atrophy (SMA). SMA, the most common cause of childhood death under two years of age, is caused by the loss of the survival motor neuron 1 gene. The absence of the gene results in progressive paralysis and muscle atrophy. Research by the Group has established that AOs to the SMN1 gene are able to induce splice switching and restore protein expression in cells from SMA patients and in a model of SMA. These studies establish proof of concept for future clinical trials in SMA patients.