USH2014 Presentations - Dr. Kerstin Nagel-Wolfrum, Therapy and Clinical Trials

Delivered by Dr. Uwe Wolfrum at the International Symposium on Usher Syndrome.

Download the presentation slides here.


The Usher syndrome (USH) is the most common form of inherited deaf-blindness with a prevalence of ~1/6,000. Three clinical subtypes (USH1-USH3) are defined according to the severity of the hearing impairment, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Currently only the amelioration of the hearing deficiency symptoms by cochlear implants is implemented, but no treatment of the senso-neuronal degeneration in the eye exists.

Patient screenings predict that ~15% of all pathogenic variants identified for USH patients are nonsense mutations. Therefore, a therapy that targets nonsense mutations could be beneficial for a substantial cohort making the approach both practical and economical. Recently, a gene based therapeutic approach for nonsense mutation-caused genetic diseases has emerged, namely the so-called read-through therapy. Nonsense mutations are caused by point mutations, which generate premature stop codons. During translation nonsense codons lead to premature translational termination of the mRNA, and subsequently to the lack of normal full-length protein expression. The read-through therapy is based on the discovery of small molecules that allow the translation machinery to recode a nonsense codon into a sense one and consequently the synthesis of functional full-length proteins. In our project, we currently focus on designer aminoglycosides and PTC124 as translational read-through inducing drugs (TRIDs).

So far, we demonstrated TRIDs induced read-through on different USH causing nonsense mutations in USH1C, USH2A and CLRN1 (USH3A) in cell culture. In addition, we observed read-through of an USH1C causing nonsense mutation in organotypic retina culture and in vivo following application of PTC124 and designer aminoglycosides. Our data indicate that the read-through efficiency is not only dependent on the mutation itself, but also on their position and the sequence context in the gene. Therefore, independent analysis of each specific USH causing nonsense mutation might be necessary before TRIDs can be applied for personalized therapy. Furthermore, our comparative analyses demonstrated the improved safety profile of designer aminoglycosides and PTC124 compared to classical aminoglycosides like gentamicin.

In conclusion, the high ocular biocompatibility combined with the sustained read-through efficacies places PTC124 and designer aminoglycosides in the spotlight for treating the progressive vision loss in USH patients carrying nonsense mutations.

Supports: German Ministry of Education and Research (E-Rare-2, the ERA-Net for Research on Rare Diseases) “EUR-USH”, EC FP7/2009/241955 (SYSCILIA); FAUN-Stiftung Nuremberg