The gene that put Australia on the map for MND research

Australia’s contribution to 30th anniversary of the discovery of the association of the SOD1 gene with MND. Written by Professor Anthony Akkari

In 1981 then Dr, now Emeritus Professor Nigel Laing, came to Western Australia to join the proposed Australian Neuromuscular Research Institute (ANRI) (now the Perron institute) to further his research into the neurobiology of motor neurones.  In the mid 1980’s, significant advances were being made in the field of genetics. In 1987, with the support of Professor Byron Kakulas, the founding Medical Director of the institute, Professor Laing travelled to Duke University in North Carolina to join the Division of Neurology to study molecular genetics and new techniques to better understand mechanisms in neurodegenerative disease. Professor Laing worked in the laboratory of Professor Teepu Siddique and with the Chief of Neurology at Duke University, the late Professor Allen Roses. Professor Roses was among the first academics to understand the power of molecular genetics in the early 1980’s [1]. Professor Roses and his team were also the first to uncover the association of the gene APOE4 with Alzheimer’s disease risk in 1993 [2]. It was with this esteemed group and Professor Siddique, who had embarked on investigating the genetics of MND, that Professor Laing trained in molecular genetics with among then the best in the field.  

In 1988 Professor Laing returned to Perth, WA and established the neurogenetics group at the ANRI, (now the Perron Institute) continuing to apply his training in molecular genetics to the study of MND, as well as to other neuromuscular diseases. Professor Laing afforded me the opportunity to join his group as a laboratory assistant in 1990 and within a short period of time I was completely captivated by the possibilities that molecular genetics methods could bring to understanding neuromuscular diseases. A few years later I enrolled as a PhD candidate in Prof Laing’s laboratory, focussing on the molecular genetics of the congenital myopathy: nemaline myopathy.  

SOD1 link to MND discovered. 

In the mid 1980’s Dr Laing with Dr Patricia Kailis, uncovered an extended Western and South Australian, multigenerational family with autosomal dominant MND – meaning that a person needs to inherit only one copy of the defective gene from one parent with the disorder to be at risk of the disease.  By 1992 Dr Laing in collaboration with Professor Teepu Siddique, was part of the international team mapping the first MND gene.  As a student I can remember Professor Laing, laying out the extensive pedigree of this family across the ANRI Board Room table; and explaining the uncertain future for family members facing the consequences of this devastating disease, hidden in their genes. “Here Tony you can see the son who passed away in his 40’s and you can see that his mother who also has MND is still alive in her 80s.” It was that particular conversation, on that day that engaged me as a student, curious and driven to research this inherited MND. Later that same year, my own father was diagnosed with MND; these two events turned me into both a neuromuscular disease researcher and carer for someone with MND. On the 4th of March 1993, Prof Laing was a member of the international team that published the discovery of the first MND gene, SOD1. The Perth family made a major contribution to the discovery, since at that time, linkage analysis was performed in a stepwise fashion, focusing on a region of the genome that was common only to people within that family that had MND. The larger and more extended multigenerational families provide a greater chance of identifying a candidate gene region linked to the inherited disorder. Importantly, within the candidate region lay the SOD1 gene. As the international research team began examining the SOD1 gene, they found the highest probability, known as a Log of the odds score or “LOD” score, occurred with the SOD1 gene. This meant that SOD1 was the most likely candidate for familial MND in the families investigated. The international team then performed subsequent studies on SOD1, looking for disease-causing mutations and found 11 different missense mutations (changes that alter one amino acid in the protein) in 13 different families from around the world, including the West Australian family. On the 4th of March 1993 the first paper describing mutations in a gene that causes MND was reported [3]. 

The discovery of the SOD1 gene as causative in MND unequivocally opened the field of MND genetics research and since this discovery, over 30 genes have been identified and are being tested on an ongoing basis for mutations in patients with clinical presentation of MND.  

Advancing novel therapeutics for neuromuscular diseases: The Perron Institute 

Professor Laing was working at the Australian Neuromuscular Research Institute (now the Perron Institute), undertaking molecular characterisations of neuromuscular disease genes. At the same institute, another team headed by Professors Steve Wilton and Sue Fletcher began working on a novel intervention, using a type of treatment called antisense oligonucleotides for the treatment of an untreatable disease called Duchenne Muscular Dystrophy (DMD). Almost 20 years later, in 2016 the first antisense therapeutic for DMD, developed by that very team, received accelerated approval from the FDA for the treatment of some individuals with that disease, providing a mutation-specific therapy for DMD. Since then, two additional therapeutics developed by Professor Fletcher and Wilton, to treat other DMD-causing mutation subgroups, were approved by the FDA.  

The SOD1 as a therapeutic target  

Upon completing my PhD and post-doctoral research with Prof Laing, I worked on neuromuscular and neurodegenerative diseases in the USA at Duke University with Professor Allen Roses and in the pharmaceutical industry, integrating genetics into drug development. I returned to Perth in 2017 and to my home, the Perron institute, to apply my industry skills to antisense oligonucleotide drug development with an urgency to improve outcomes for patients living with MND. 

Shortly after my return, I was privileged to meet Dr Loren Flynn, who trained in the laboratory of Professors Wilton and Fletcher and with over 14 years of experience in these novel antisense therapeutics. Dr Flynn agreed to join the newly established MND genetics and therapeutics group at the Perron Institute and lead the antisense development programs targeting MND disease mechanisms. Dr Flynn’s first interest was to develop a SOD1 targeting program using an antisense therapeutic approach, in collaboration with Professors Wilton, Fletcher and myself. Dr Flynn, with exceptional support from our colleague Professor Bradley Turner (Florey Neuroscience Institute) and Black Swan Pharmaceuticals, an MND antisense drug development company, has advanced this drug for SOD1 MND patients toward the clinic. This collaboration led to the achievement of our first major milestone in taking our therapeutic toward the clinic with a $1M Drug Development grant awarded by our partners FightMND in 2020. This funding has been instrumental in advancing the SOD1 therapeutic. With funding from FightMND as well as industry support, we are moving efficiently toward clinical trials, with additional antisense therapeutics to follow.  

The first MND-linked disease gene, SOD1 was discovered through research undertaken in Australia, in collaboration with Australian patients. Now, a promising drug is under development in Australia, by Australian researchers, funded by Australians.  

Researchers worldwide continue to make significant progress in understanding MND and the role of genetics in the disease. In April 2023, the FDA approved the first antisense therapy for MND, a SOD1 suppression drug called Tofersen. This is as exciting time for genetic therapies for MND as it paves the way for future discoveries and translation of other novel antisense therapies. We are, as a global community, collaborating, sharing, and learning from each other how to progress toward successful therapies for MND. Researchers from across Australia are working together, looking beyond the horizon, and imagining better ways to understand, diagnose, model and develop therapeutics for this dreadful disease.  

THANK YOU 

I would like to personally thank MND patients around the world and in Australia FightMND, The Giumelli Family, The Perron Institute and Murdoch University, MNDRIA, MSWA, Black Swan Pharmaceuticals, and our associated investor/philanthropists, racing for MNDi, as well as our collaborators in Australia; Professor Bradley Turner and the Florey Neuroscience Institute, and our international collaborators. We are very privileged to work with a committed community determined to advance disease-modifying therapeutics for MND.  

Professor Anthony Akkari is the Co-Lead of the Motor Neuron Disease Genetics and Therapeutics group at the Perron Institute for Neurological and Translational Science, and the Foundation Chair of Industrial Pharmacogenetics at Murdoch University. He is also the Chief Scientific Officer and a Co-Founder of Black Swan Pharmaceuticals, a pharmaceutical company developing antisense therapeutics for MND and Parkinson’s Disease.  

 References

1. Snyder A: Allen Roses. Lancet 2016, 388(10057):2232.
2. Strittmatter WJ, Weisgraber KH, Huang DY, DONG L-M, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD: Binding of human apolipoprotein E to synthetic amyloid ,Bpeptide: Isoform-specific effects and implications for late-onset Alzheimerdisease. Proc Natl Acad 1993, 90:8098-8102. 
3. Rosen R, Siddique T, Patterson D, Figlewicz D, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan J, Deng HX et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362:59-62.