Project Title

Exon skipping as a novel therapeutic for restoring Factor VIII levels.

Project Summary

Haemophilia A (HA) is a bleeding disorder resultant from mutations in the coagulation protein, Factor VIII, or the presence of inhibitory autoantibodies. Together, with Factors IXa and X, Factor VIII is vital in preventing blood loss at the site of injury.

Severe HA is defined as having little (<1units/dL), or no FVIII. It is associated with a significant bleeding phenotype that can be life-threatening in surgical settings and can lead to haemarthrosis. Traditionally, HA has been treated with externally isolated Factor VIII – however, over time patients will develop inhibitors against the foreign Factor VIII therapy, essentially nullifying the treatment.

A DNA strand that encodes human genes is made up of exons and introns, and this genetic code contributes to the production of the functional Factor VIII protein containing only the exon sequences.

Mutations to the F8 gene results in HA, and different mutations cause different severities of the disorder. HA patients have defects in selected F8 exons, and mutation clusters are often common in patients.

This research hypothesizes that mutated exons/sequences can be excluded from the final protein product, and still produce a functional truncated protein. To this end, we tested the feasibility of an Exon-skipping therapeutic strategy first established in the treatment of Duchenne’s Muscular Dystrophy.  Exon 14 of the F8 gene was chosen as a target for the proof-of-concept experiments.

This project aims to restore Factor VIII protein functions by correcting the mutations with next generation therapeutics. 

Blood Disorder

• Haemophilia A

Patient Recruitment Details

Patient recruitment status: Not recruiting (in-vitro study only).

Number of Patients

N/A

Supporting Organisations

N/A