Posts tagged Usher syndrome
Articles and news from the latest research reports.
Hearing protein required to convert sound into brain signals
A specific protein found in the bridge-like structures that make up part of the auditory machinery of the inner ear is essential for hearing. The absence of this protein or impairment of the gene that codes for this protein leads to profound deafness in mice and humans, respectively, reports a team of researchers in the journal EMBO Molecular Medicine.
“The goal of our study was to identify which isoform of protocadherin-15 forms the tip-links, the essential connections of the auditory mechanotransduction machinery within mature hair cells that are needed to convert sound into electrical signals,” remarks Christine Petit, the lead author of the study and Professor at the Institut Pasteur in Paris and at Collège de France.
Three types of protocadherin-15 are known to exist in auditory sensory cells of the inner ear but it was not clear which of these protein isoforms was essential for hearing. “Our work pinpoints the CD2 isoform of protocadherin-15 as an essential component of the tip-link and reveals that the absence of protocadherin-15 CD2 in mouse hair cells results in profound deafness.”
Within the hair bundle, the sensory antenna of auditory sensory cells, the tip-link is a bridge-like structure that when stretched can activate the ion channel responsible for generating electrical signals from sound. Tension in the tip-link created by sound stimulation opens this channel of unknown molecular composition thus generating electrical signals and, ultimately, the perception of sound.
The researchers engineered mice that lack only the CD2 isoform of protocadherin-15 exclusively during adulthood. While the absence of this isoform led to profound deafness, the lack of the other protocadherin-15 isoforms in mice did not affect their hearing.
Patients who carry a mutation in the gene encoding protocadherin-15 are affected by a rare devastating disorder, Usher syndrome, which is characterized by profound deafness, balance problems and gradual visual loss due to retinitis pigmentosa. In a separate approach, the scientists also sequenced the genes of 60 patients who had profound deafness without balance and visual impairment. Three of these patients were shown to have mutations specifically affecting protocadherin-15 CD2. “The demonstration of a requirement for protocadherin-15 CD2 for hearing not only in mice but also in humans constitutes a major step in the objective of deciphering the components of the auditory mechanotransduction machinery. This isoform can be used as a starting point to identify the other components of the auditory machinery. By focusing our attention on the CD2 isoform of protocadherin-15, we can now consider developing gene therapy strategies for deafness caused by defects in this gene,” says EMBO Member Christine Petit.
Scientists prevent development of deafness in animals engineered to have Usher syndrome
Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns, and yet there is no physiological cure for children who are born deaf. Most cases of congenital deafness are due to a mutation in a gene that is required for normal development of the sensory hair cells in the inner ear that are responsible for detecting sound. To cure deafness caused by such mutations, the expression of the gene must be corrected, a feat that has been elusive until recently.
Rosalind Franklin University of Medicine and Science (RFUMS) Assistant Professor Michelle Hastings and her team, along with investigators at Louisiana State University Health Sciences Center in New Orleans, Louisiana and Isis Pharmaceuticals in Carlsbad, CA, have now found a way to target gene expression in the ear and rescue hearing and balance in mice that have a mutation that causes deafness in humans. The results of the study are reported in the paper, Rescue of hearing and vestibular function in a mouse model of human deafness, which was published February 4, 2013 in the journal Nature Medicine.
Dr. Hastings collaborated with research leaders across the country, including RFUMS colleagues Francine Jodelka and Anthony Hinrich, who were co-first authors on the study, as well as Dr. Dominik Duelli and Kate McCaffrey; co-first author Dr. Jennifer Lentz at Louisiana State University Health Sciences Center New Orleans, and Dr. Lentz’s research team, including Drs. Hamilton Farris and Nicolas Bazan and Matthew Spalitta; and Dr. Frank Rigo at Isis Pharmaceuticals. The collaboration led to the development of a novel therapeutic approach to treat deafness and balance impairment by injecting mice with a single dose of a small, synthetic RNA-like molecule, called an antisense oligonucleotide (ASO). The ASO was designed to specifically recognize and fix a mutation in a gene called USH1C, that causes Usher syndrome in humans. The ASO blocks the effect of the mutation, allowing the gene product to function properly, thereby preventing deafness.
Usher syndrome is the leading genetic cause of combined deafness and blindness in humans. Treatment of these Usher mice with the ASO early in life rescues hearing and cures all balance problems. “The effectiveness of the ASO is striking,” states Hastings. “A single dose of the drug to newborn mice corrects balance problems and allows these otherwise deaf mice to hear at levels similar to non-Usher mice for a large portion of their life,” she says.
Validating ASO efficacy in the Usher mice is an important step in the process of developing the strategy for human therapy. Dr. Lentz, who has been studying Usher syndrome for almost 10 years and engineered the mice to model the human disease, states, “Successfully treating a human genetic disease in this animal model brings the possibility of treating patients much closer.”
The results of the study demonstrate the therapeutic potential of this type of ASO in the treatment of deafness and provide evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression.
"The discovery of an ASO-type drug that can effectively rescue hearing opens the door to developing similar approaches to target and cure other causes of hearing loss," says Dr. Hastings who has been awarded a grant from the National Institute of Health to further develop the ASOs for the treatment of deafness with Drs. Lentz, Rigo and Duelli.
(Source: eurekalert.org)