FOP

Nucleic Acid Ther. 2022; 32(3):185-193.

Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal-dominant disorder characterized by progressive heterotopic ossification in skeletal muscle, tendon, and soft connective tissues. The median lifespan of patients is around 40 years of age. The disorder is caused by mutations in the ACVR1/ALK2 gene, a bone morphogenetic protein (BMP) type I receptor. Palovarotene (brand name Sohonos) is the first treatment for FOP that has been approved in Canada in 2022. However, the drug has limitations such as failure in a clinical trial, being placed under a partial clinical hold by the FDA, and not being able to distinguish between wild-type and mutant ACVR1 receptors, leading to potential harm.

Our current study aims to develop a new therapy using antisense oligonucleotides (AONs) that can specifically target the mutant ACVR1 receptor without impairing wild-type ACVR1 activity. To do this, we are developing gapmers that include a mismatched base in the sequence to increase allele specificity. Our study has shown that gapmers effectively knocked down the mutated ACVR1R206H mRNA while leaving healthy mRNA unaffected in patient cells. We are currently testing the efficacy and safety of these gapmers in a humanized FOP mouse model. The identification of highly effective gapmers and LNPs will open the door for future clinical translation of antisense therapy for FOP patients and encourage the development of allele-specific antisense therapies for other genetic diseases.

Last updated: 1 October, 2023