Gene therapy shows potential as Usher syndrome treatment

Translational read-through inducing drugs get past stop codons in type 1c

Researchers from Germany report promising data on a potential gene therapy for a severe form of Usher syndrome.

Usher syndrome is the most common form of genetic deaf- blindness. Patients with type 1, the most severe form, are born deaf and suffer slow retinal degeneration, which accelerates at puberty and progresses to complete blindness. It is possible to offset hearing loss with hearing aids and cochlear implants, but no approved therapy improves vision.

Figure 1.

While gene therapy sometimes involves delivering replacement genetic material via viruses, translational read-through inducing drugs (TRIDs) may be useful for particular culprit mutations involving premature stop codons.

A stop codon is a series of three messenger RNA (mRNA) nucleotides that signal the end of translation. If a stop codon is premature, a protein isn't expressed correctly and is likely nonfunctional. TRIDs induce RNA machinery to replace the stop codon with an amino acid so protein synthesis can continue.

In EMBO Molecular Medicine, a Johannes Gutenberg University Mainz team led by Kerstin Nagel-Wolfrum, PhD, describes the TRIDs NB54, NB30, and PTC124, also known as Ataluren, as promising agents in correcting a stop codon mutation at p.R31X in the USH1c gene, which encodes the scaffold protein harmonin and is a mutation in Usher syndrome type 1c. The drugs don't appear to cause toxicity and promote read through of the premature stop codon, their study says (Goldmann et al., 2012).


Because toxicity was a problem with early TRIDs, the researchers monitored potential toxic effects of the three drugs on the retina using cell-specific molecular markers to analyze retinal integrity and possible TRID-induced cell death in retina cultures. They found no evidence of damage indicating toxicity in the retinal structure or the specific cell types after application of all three TRIDs. Researchers also tested the biocompatibility of TRIDs in human retinal explants cultured from human donor eyes post-mortem. NB54 and PTC 124 were more biocompatible than NB30 in the retina, they found.

After examining read-through efficacies of the applied TRIDs on the USH1C p.R31X mutation in cell culture, retinal explants, and in vivo, the researchers found that all three drugs induced translational read-though of the p.R31X mutation to some degree. NB54 was the most successful in culture, with 3.7% of total harmonin expression, compared to 2.1% and 2.5% for NB30 and PTC124, respectively, the researchers report. However, the drugs' in vivo read-through efficacy was about equal.

Promise and Challenges

William Kimberling, PhD, Director of the Center for the Study and Treatment of Usher Syndrome in Omaha, Nebraska, says these TRIDs have great potential because they target “a specific type of mutation, rather than a specific gene, and thus should have applicability to other genetic disorders as well.” For Usher syndrome type 1c, the value of these drugs hinges on answers to such questions as whether the amount of functional protein produced with the help of these TRIDS is enough to rescue the phenotype.

“The assumption is that a meagre expression is all that is needed to restore harmonin to clinical effectiveness,” Dr. Kimberling explains. “Presumably, once the amount of protein produced falls below some threshold level, disease results.”

If the threshold is 1%, then a TRID that increases the expression of the gene to 3% is likely to be effective, but it wouldn't work well if the threshold is 5% or higher, for example. This issue gets more complicated in patients who are compound heterozygotes, who usually have both a missense mutation and a splice, Dr. Kimberling adds.

It's not known which amino acids replace stop codons in the small proportion of proteins produced after TRID use, adds otolaryngologist Richard Smith, MD, Director of the Iowa Institute of Human Genetics at the University of Iowa in Iowa City. “Some may be the right amino acids, others are benign, and others could result in a situation as bad as what results from lack of read-through,” Dr. Smith says. To be clinically useful, the restored harmonin protein must be of sufficient quality to function not only in culture, but also in the cell, where it must interact well with several other proteins, he notes.

Dr. Kimberling hopes TRIDs result in a viable clinical therapy that will be available to affected children shortly after diagnosis. Retinal decay in Usher 1c patients is significant during childhood, but by age 20, most are legally blind, he notes. “TRID treatment given systemically may preserve both vision and hearing, or at least slow the progression at a time when it is at its most rapid,” he adds.