Watch Dr Emily Oates accept the research grant award and hear a bit about the project.
Recessive titinopathy has recently emerged as one of the most common childhood-onset muscle disorders. It is caused by disease-causing variants within an enormous gene called TTN (titin) and results in weakness of the voluntary skeletal muscles of the body, such as the arm, leg, and breathing muscles, and the heart muscle. This results in physical disability and sometimes early death, usually due to breathing or heart complications. There are no effective treatments to prevent or reduce the significant and often-progressive weakness caused by this condition.
Differences in the amount of titin protein expressed in patient muscle are likely contributing to the striking differences in clinical severity observed within this patient group (some succumb during pregnancy/infancy, others survive into adulthood). We anticipate that patients who express more titin are less severely affected. Therefore, increasing titin expression is likely to improve patient outcomes. However, existing titin quantification methods are notoriously inaccurate.
We currently have funding to develop two different treatment strategies (CRISPR-on and exon skipping) aimed at increasing titin expression. This project will complement these treatment development endeavours by enabling us to develop and apply a novel mass spectrometry-based method to accurately quantify titin expression in patient muscle from mildly and severely affected individuals and compare this to expression in healthy muscle. This will increase our understanding of how much additional titin is needed to improve clinical outcomes. The project will also allow us to characterise the impact of disease-causing variants at the protein recipe (RNA) level to better understand which patients would benefit most from our exon skipping therapies. Overall, this project will advance our goal of becoming a world leading recessive titinopathy treatment development centre.