Jennifer Lentz from New Orleans (LSU School of Medicine, USA) is working on a treatment for USH1C patients who have a specific mutation in the USH1C gene, the c.216G>A mutation.
The USH1C gene is translated into the harmonin protein, which plays an important role in the eye, ear and balance organ. The c.216G>A mutation influences the pre-mRNA splicing. As a consequence of this mutation a part of the USH1C gene is not included in the mRNA. If this part of the USH1C gene is missing in the mRNA, the production of the harmonin protein stops prematurely. This incomplete harmonin protein is not functional, which leads to retina degeneration, loss of hearing and imbalance problems.
Lentz and colleagues have developed an antisense oligonucleotide for this specific mutation. An antisense oligonucleotide, abbreviated by ASO or AON, is also called a ‘genetic patch’. Dependent on the design an antisense oligonucleotide may have different functions. The ‘genetic patch’ can skip the stop coding (exon skipping) or correct the splicing (splice correction). ASO29, the antisense oligonucleotide of Lentz, corrects the pre-mRNA splicing. All important information of the USH1C gene is included in the mRNA again and the cell can restart the production of the harmonin protein.
A few years ago, Jennifer Lentz was able to demonstrate that the balance of new-born mice with the c.216G>A mutation in the USH1C gene was recovered after administration of ASO29. The hearing of these mice improved as well after treatment with the genetic patch. The cochlea and the organ of balance of people are difficult to reach using medicines.
Currently, a study is being conducted into how to best administer the genetic patches. Recently, the effect of the genetic patch on retina degeneration was studied as well. A local injection of this medicine in the vitreous of the eye also seems to improve the visual function. All studies are presently still conducted on animal models and they are promising in particular with respect to the eye.
In October 2019, Jennifer Lentz, in partnership with Robert K. Koenekoop of McGill University in Montreal, Canada, received a $ 1.74 million grant to advance the research. With this grant, they want to test USH 1C-specific ASOs with different sequences for efficacy and tolerance in USH1C mice and patient cells. “
Update 7 September 2020:
During the USH Connect week in July 2020, organized by Usher Syndrome Coalition, Jennifer Lentz gave a presentation ‘Update research USH1C’.