HFI Public Lecture - Prof Anthony Akkari and Prof Steve Wilton

Venue: Boola Katitjin - B360.4.003

SPEAKER BIO - Professor Anthony Akkari

Professor Akkari is a pharmacogeneticist and neuromuscular geneticist with over 30 years of research experience in Australia and the US. He completed his PhD in neuromuscular disease genetics at Curtin University, later undertaking postdoctoral research at Duke University, Division of Neurology, where he continues his ongoing collaborations and is an Adjunct Professor. Since moving back to WA, Anthony has established a vibrant research group focusing on motor neurone disease (MND), which he now co-leads with Dr Loren Flynn. The dually based Motor Neurone Diseases Genetics and Therapeutics group at Murdoch’s Centre for Molecular Medicine and Innovative Therapeutics (CMMIT) and the Perron Institute are focused on how genetic variation within the human genome contribute identifying subgroups of patients with sALS and how these can be co-developed with therapies for improving the success of ALS clinical trials. Professor Akkari’s industry experience includes a history in the USA pharmaceutical industry at GSK, and later Eli Lilly and Cabernet Pharmaceuticals, where he focused on integrating genetic data into the drug development to drive stratified medicines for patients. Professor Akkari is currently the Chief Scientific Officer and co-founder of Black Swan Pharmaceuticals, an ALS drug development company. Anthony is the Foundation Chair of Industrial Pharmacogenetics at Murdoch University and was appointed as Centre Director of CMMIT in March 2023. Anthony has served on the board of the Motor Neurone Disease Association of Western Australia for the last 3 years and was invited to be the Western Australian State Representative to the Motor Neuron Disease Collective of Australia.

SPEAKER BIO - Professor Steve Wilton AO

Professor Wilton is Foundation Professor of Molecular Therapy at Murdoch University and has the dual roles of Deputy Director of Murdoch's Centre for Molecular Medicine and Innovative Therapeutics (CMMIT) and Director of the Perron Institute for Neurological and Translational Science, Western Australia's oldest medical research institute.

Steve joined the Australian Neuromuscular Research Institute – the predecessor of the Perron Institute – in 1991 and embarked on a research journey that culminated in the development of life-changing drugs for the treatment of Duchenne muscular dystrophy. The novel concept of dystrophin exon skipping using antisense oligonucleotides to treat Duchenne arose out of Steve’s research on diagnostic screening for neuromuscular diseases. Along with colleague Sue Fletcher, he has pioneered the use of antisense oligonucleotide-based drugs to treat Duchenne for over 20 years, with his group being the first to report specific exon skipping in an animal model of Duchenne, a finding that over time led to the development of a complete panel of splice switching antisense oligonucleotides covering potentially over 80% of Duchenne cases. He was the first to recognise the greater efficacy in vivo of phosphorodiamidate morpholino oligomers as splice switching agents, which are now seen as the chemistry of choice for in vivo exon skipping in Duchenne and other patients.

Steve’s group designed the first morpholino oligomer targeting exon 51 in the dystrophin gene, eteplirsen (Exondys 51) and working in partnership with the US company, Sarepta Therapeutics showed that it restores dystrophin expression and slows disease progression in Duchenne patients. This compound was given accelerated approval by the US Food and Drug Administration (FDA) in 2016 and is now in use in patients. A second compound, Golodirsen (Vyondys 53) targeting exon 53 using a sequence designed by Steve’s group was granted FDA approval in late 2019 and yet a further drug, Casimersen (Amondys45) was granted FDA approval in February 2021. The three drugs – Exondys 51, Vyondys 53 and Amondys 45 – provide clinicians with the tools to treat over a quarter of Duchenne cases.

Steve’s research has been recognised by multiple awards, including the 2012 Western Australian Innovator of the Year award, the 2013 Australian Museum Eureka Award for Translational Medicine and the 2014 LabGear Discovery Award. In 2021, Steve was made an Officer of the Order of Australia (AO) for distinguished service to medical research, to neurological science and to the treatment and support of those with muscular dystrophy.

In 2013, he was appointed Director of the Perron Institute in 2013 coincident with him becoming the Foundation Chair in Molecular Therapy at Murdoch University. From 2019 – early 2023, Steve took on the role of Director of Murdoch’s Centre for Molecular Medicine and Innovative Therapeutics (CMMIT) ((Now Deputy Director), which forms part of Murdoch’s Health Futures Institute.

Steve and his group continue to actively collaborate with Sarepta Therapeutics in developing and refining antisense oligomers targeting the dystrophin gene. He is currently extending his research on the therapeutic applications of antisense oligomers to other inherited and acquired conditions, including other muscular dystrophies, cystic fibrosis, motor neurone disease, multiple sclerosis, Alzheimer’s, Pompe’s disease, congenital muscular dystrophy, Huntington’s, asthma and neuroinflammatory conditions.

ABSTRACT - Quokkas, Mice, Zebras and Humans: Perth’s place in Medical research

Despite its reputation as the world’s most isolated capital city, Perth has played prominent roles in medical research. More than 50 years ago, Byron Kakulas demonstrated that it was possible to reverse a fatal muscle wasting disease in Rottnest Island’s quokkas. This was contrary to established medical dogma at the time and suggested that muscle regeneration is possible even in diseases such as muscular dystrophy. This revolutionary finding opened up a new field of research, one consequence of which was the establishment of Perth’s oldest medical research institute, the Perron Institute for Neurological and Translational Science. The Perron was established with a special focus on Duchenne muscular dystrophy (DMD), the most common and serious form of childhood muscle wasting. In parallel to the Perron’s research on DMD, Professor Nigel Laing, was leading gene mapping efforts in large families to identify a mutated gene causing particular neuromuscular diseases, other forms of muscular dystrophy and most importantly linking the first gene, SOD1 with motor neuron disease (MND).

The first step in designing any therapy for a disease is establishing what has gone wrong and identifying the disease mechanism and pathogenic pathways so that rational interventions can be designed and validated. These studies are usually done in cell cultures derived from the affected individual and then later validated in animal models, most commonly mice in the initial phase. This is what happened with the development of three FDA approved drugs to treat individuals suffering from DMD. Rather than replacing the defective gene, Perth-based researchers came up with a “gene patch” system that allows the patient’s cells to skip over the disease-causing mutation. While not a cure, the FDA-approved drugs tailored to three of the most common types of different spelling errors causing DMD, greatly reduce disease severity and are in daily use in patients. Clinical trials are ongoing to further improve efficiency and address other disease-causing spelling errors, not just in the gene associated with DMD but in other diseases.

Having demonstrated the natural history of DMD disease progression could be altered, it became apparent that the gene patch technology could be applied equally to many other conditions: from other muscular dystrophies to asthma, from Parkinson’s to motor neuron disease. Perhaps the greatest potential of the gene patches lies with their flexibility to be used for many different types of mutations, in particular rare and ultra-rare diseases that are a particular focus of the Centre for Molecular Medicine and Innovative Therapies. With some 7,000 different rare diseases described to date, 80% of which have a single gene basis, the impost and cost of rare disease on the community is an enormous health issue and one that does not get the attention it deserves. Zebras have been chosen as the symbol for some rare diseases, and you will find out why at the end of the presentation.