Leukodystrophy

Over one hundred new adult and paediatric patients present with leukodystrophies in Australia annually. However, until recently approximately half of cases presenting with these debilitating conditions remained unsolved.

    Massimo’s Mission Leukodystrophy Program

    A clinical and research program which promotes the prevention, diagnosis and treatment of leukodystrophies.

    Although genomics is successfully identifying new rare diseases by unlocking their previously unknown causes, diagnosis is only the first step. There is currently no established translational pathway to treatment for newly discovered diseases. The search for treatments is happening one rare disease at a time.

    In July 2009, Massimo Damiani presented with a mysterious neurological condition, broadly known as leukodystrophy, in which the wires of his brain were losing their protective insulation (myelin) causing him to lose skills. After months of exhaustive, and often invasive testing, the science of the day could offer no answers. Without a specific genetic diagnosis there was no hope of developing a treatment for Massimo.

    In 2010 an Australian-led research team, pioneered a new “trio whole genome” sequencing approach, and were, in a world-first, able to establish that Massimo’s condition was caused by mutations in the DARS gene. The team described a new disease: ‘hypomyelination with brain stem and spinal cord involvement and leg spasticity’, or HBSL and discovered its genetic cause in a gene not previously associated with disease. However, as with many other rare diseases, there was no pathway to translate this diagnostic knowledge into a new clinical treatment.

     

    Massimo’s Mission leukodystrophy program focuses on two key areas:
    1. Providing a genetic diagnosis for Australian families affected by leukodystrophies. Through this program, we will offer clinical and/or research based genomic testing for undiagnosed children and adults with a leukodystrophy living in Australia.
    2. Piloting the rapid development of cell and animal models of leukodystrophies to use these models to perform pre-clinical testing of candidate targeted therapies.

    The Massimo Mission will be administered in conjunction with the Australian Genomics Leukodystrophy Flagship.

    If you would like to be involved or you would like to refer someone to the program please complete the expression of interest survey through the link below:

    https://redcap.mcri.edu.au/surveys/?s=33YKYRRMWE

    For further information or to enrol please contact clinical research coordinator Eloise Uebergang on +61 3 8341 6382 or leukonet@mcri.edu

    Royal Children’s Hospital and the Murdoch Children’s Research Institute.

    Application of state of the art genomic technologies will provide faster diagnoses for Australians and aims to reduce the proportion of undiagnosed leukodystrophies to < 10% by 2020.

    1. Clinical Genomics (EWACS)

    The program will offer clinical genomic testing to children with undiagnosed leukodystrophies through the leukodystrophy and other white matter disorders clinic at the Royal Childrens Hospital. We will use the latest genomic sequencing technology to provide the most comprehensive analysis of all clinically relevant genes for rapid diagnosis of leukodystrophies.

    2. Research genomics (PRISM)

    Children and adults with an undiagnosed leukodystrophy can be offered research based genomic testing and/or analysis through the Murdoch Childrens Research Institute. We will utilise advanced genomic technologies including a familial trio approach to help to identify new genetic causes of leukodystrophies.

    3. The Australian Leukodystrophy Registry (BLACKJACK)

    Children and adults with a diagnosed or undiagnosed leukodystrophy can be added to our new registry. The registry will collect clinical and imaging data and test results from medical records. Registries are essential to help understand rare diseases and for developing new treatments. Being included on the registry will enable participation of Australian patients in international leukodystrophy research through the Global Leukodystrophy Initiative (GLIA) and other collaborative efforts.

    4. Disease modelling

    To help establish a translational pathway for the development of clinical treatments, Massimo’s Mission will use HBSL to help build local capabilities in the rapid cell and animal modelling of rare genetic diseases.

    Stem cell models (PROMETHEUS)

    The Wolvetang Laboratory (University of Queensland) is utilising cutting-edge induced pluripotent stem cell technology to offer unprecedented possibilities in modelling human diseases, literally in a dish. Multiple patient derived induced pluripotent cell lines across the disease spectrum of HBSL have already been created and we are expanding this repertoire. Although just being used in disease modelling for now, CRISPR corrected patient derived induced pluripotent stem cells show great promise to treat neurological diseases which have previously been considered untreatable without immunological rejection.

    Animal models (MASSIMOUSE and MIYAIMOUSE)

    The Klugmann Laboratory (UNSW) has created the MASSIMOUSE, a patient matched HBSL mouse model of Massimo, providing a secondary model of the disease to understand pathogenic mechanisms and test potential therapeutics options. The MIYAGIMOUSE is a genetically engineered knock-out mouse that allows for cross breeding with the MASSIMOUSE to better understand pathogenicity.

    5. Pre-Clinical testing

    The program will test possible therapeutics that have been identified and developed on patient derived stem cells and corresponding mouse models.

    Gene therapy (JOINT STRIKE VECTOR)

    The Kluggman Laboratory (UNSW) has created an Adeno Associated Virus (AAV) gene therapy platform, capable of correcting genetic mutations with no immune response. This delivery platform can infect only dividing cells without integrating into the genome of the host cell, making it an attractive candidate for gene therapy and for the creation of human disease models with minimal risk of rejection.

    CRISPR (GENESIS)

    The Wolvetang Laboratory (University of Queensland) is utilising CRISPR editing techniques to correct mutations on patient derived induced pluripotent stem cells. These CRISPR corrected patient derived cells can be tested across multiple disease models and ultimately be reintroduced to treat disease without the risk of rejection.

    6. Human clinical trials (THUNDERBIRD)

    We aim to ‘complete the mission’ with the promise of human clinical trials with precision treatments. The success of Massimo’s Mission depends each of the steps that began before it beginning and ending with the patient and their clinicians.

    “Tragically, Massimo passed away on Friday 15th December 2017 leaving this Earth far too soon. Precision treatments for these terrible diseases are truly within our grasp. Today’s, funding announcement is a fitting tribute to honour Massimo’s legacy and will support pioneering Australian research to finish the mission he started.”

    Stephen Damiani – Mission Massimo Foundation

    Who’s involved?

    Leads
    A/Prof Richard Leventer
    Murdoch Children’s Research Institute & The Royal Children’s Hospital

    Dr Cas Simons
    Murdoch Children’s Research Institute

    Prof Ernst Wolvetang
    The University of Queensland

    Prof Matthias Klugmann
    University of NSW

    Research Coordinator
    Eloise Uebergang
    Murdoch Children’s Research Institute

    Victoria
    Dr Chloe Stutterd
    Murdoch Children’s Research Institute & The Royal Children’s Hospital

    Dr. Victoria Rodriguez-casero
    The Royal Children’s Hospital

    Stephen Damiani
    Mission Massimo Foundation

    New South Wales
    Dr. Dominik Froehlich
    University of NSW

    Queensland
    Dr. Mohammed Shaker
    University of Queensland

    South Australia
    Dr. Nick Smith
    Women’s and Children’s Hospital

    “This program is supported by the Leukodystrophy Flagship Massimo’s Mission, funded by the Medical Research Future Fund (ARG76368).”

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