Treating inherited brain disease in children

Biology, biomedical science and biotechnology

This genetics and molecular pathology project explores the use of gene therapy to treat inherited brain disease in children.

Inherited brain disorders present throughout life although disease burden is greatest in childhood. Neurological regression is relentless with a loss of acquired skills – e.g. the ability to speak, walk, eat - and a devastating impact on the child and family. 

There is no cure and as yet no treatment for the progressive decline in brain function.

Gene therapy has held promise for treating such diseases by replacing the defective gene with a functional one. The first-in-man gene therapy trial for the inherited neurodegenerative disease known as mucopolysaccharidosis type IIIA (MPS IIIA) is underway. 

Our laboratory is heavily involved with this clinical trial by measuring disease biomarkers from these patients to assess therapeutic efficacy of the gene therapy treatment. MPS IIIA is often considered the prototype for inherited neurodegenerative metabolic disease and, like all of these diseases, is progressive. This means that any treatment – including the aforementioned gene therapy trial – is challenged with treating residual pathology that is already entrenched and considered irreversible. At best then, treatment may only be able to halt disease progression and stabilise the disease.

We are performing a number of parallel studies in mouse and cell models of inherited metabolic disorders, including the MPS IIIA mouse, to learn more about the progression of the neurological process and the irreversibility of disease. Gene therapy vectors are administered to MPS IIIA mice at different ages, representing different stages of residual disease burden, and the brains removed for biochemical and molecular testing. Memory and learning are also measured in mice as an assessment of cognitive improvement.

Biochemical assessments can then be translated to cerebrospinal fluid and blood which are being collected from the human trial to evaluate the biochemical changes seen in the mice model with those in treated patients. 

Additional studies in cell models, including neuronal cultures, can inform on mechanisms of disease to learn more about the neurodegenerative decline and open up new avenues for treatment and adjunct therapies to complement gene therapy approaches.

The outcomes will inform on the timing and efficacy of gene therapy as well as increase our understanding of the neurodegenerative process in order to explore new therapeutic approaches for existing pathology that is not reversible with contemporary gene therapy.

Gene therapy trial information

Supervisor

Tagged in Honours projects - Molecular and biomedical science, Honours projects - Chantelle McIntyre, Honours projects - Molecular and biomedical science: Genetics, Honours projects - Maria Fuller