Antisense oligonucleotides for the treatment of inherited deafness DFNA9

DFNA9 is a relatively common form of adult-onset, autosomal dominantly inherited, progressive hearing loss. DFNA9 is caused by mutations in the COCH gene, and leads to complete deafness by the age of 50-70. DFNA9 patients furthermore suffer from severe balance loss, hampering their daily movements. Dominant COCH mutations result in the formation of cytotoxic protein aggregates, consisting of both mutant and normal COCH proteins, that interfere with hearing and balance function.

Currently, no effective treatment is available to prevent or delay the loss of hearing and balance problems in DFNA9 patients. Antisense oligonucleotides (AONs) are small synthetic single-stranded DNA/RNA molecules that can be used target pre-mRNA for degradation. In a dominantly inherited disorder such as DFNA9, they can be used to specifically degrade mutant COCH transcripts and/or block the translation of mutant COCH protein thus preventing the formation of cytotoxic protein aggregates.

To develop AONs with high specificity for the mutant allele, we first used long-read haplotype sequencing to identify all mutant-allele specific variants that can serve as therapeutic targets for the majority of patients carrying the c.151C>T(p.P51S) and c.263G>A (p.G88E) founder alleles.

We obtained proof-of-concept that both a disease-causing variant, and mutant allele-specific variants, can be used as potent discriminating variants to specifically decrease mutant COCH transcript levels, without interfering with wildtype transcript levels. An example of this is provided in Figure 1.

Applications

• Ophthalmology
• Stargardt disease
• Antisense oligonucleotide therapy

Development status: Proof of concept

• We obtained proof-of-concept in cells expressing mutant and wildtype COCH alleles, and are working on the preclinical lead optimization in preparation of a clinical use.
• Additional mutant allele-specific variants on the c.151C>T(p.P51S) and c.263G>A (p.G88E) founder alleles will be analyzed for their eligibility as targets for AON-based therapy.

Opportunity

• We offer a licensing opportunity of the patent covering the described invention.
• We are interested in collaboration and/or co-development of the invention.

Contact

For more information contact us through businessdevelopment@radboudumc.nl.