Novel genetic patch may help treat hereditary deafness, cIaims study

These patches contain Antisense oligonucleotides with DNA-like properties which can be employed to target (pre-)mRNA molecules for degradation by the RNase H1 endonuclease. The ability of antisense oligonucleotides (AONs) to specifically target mutant transcripts for 249 degradation is of key importance for the development of an AON-based therapy for 250 dominantly-inherited disorders with a dominant-negative or gain-of-function disease 251 mechanism such as DFNA9. The therapeutic strategy must be potent enough to prevent the 252 synthesis of proteins from the mutant allele, but allow sufficient protein synthesis from the 253 wildtype allele for normal inner ear function.

Working further on cellular levels , the team noted that the patch was effective when applied to cultured cells."The c.151C>T (p.Pro51Ser) founder mutation, affecting the LCCL domain, appears to be the 68 most prevalent mutation in COCH, as it underlies hearing loss in >1000 Dutch and Belgian individuals. All available data indicates that DFNA9 results from a gain-of-function and/or a dominant negative disease mechanism, rather than from haploinsufficiency. Downregulation of the mutant allele, thereby alleviating the inner ear from the burden caused by the formation of cytotoxic cochlin dimers, therefore has high therapeutic potential."the team observed.

The transient effect of AONs is both an advantage and a potential limitation for future clinical applications. It lowers the risk of sustained adverse or off-target effects that could accompany genome editing techniques, but it also implies that a repeated delivery is likely to be required to achieve maximum efficacy.

For the full article follow the link: Erik de Vrieze et al, Antisense oligonucleotide-based degradation of c.151C>T mutant COCH transcripts associated with dominantly inherited hearing impairment DFNA9., Molecular Therapy - Nucleic Acids (2021). DOI: 10.1016/j.omtn.2021.02.033

Primary source: Molecular Therapy