Treatment approach to human Usher syndrome: Small molecules ignore stop signals
Fluorescence microscopic analyses of cells carrying a nonsense mutation in the USH1C gene. In the left cell, no translational readthrough has occurred. In the right cell, PTC124 mediated translational readthrough of the USH1C nonsense mutation resulted in the restoration of harmonin's (green) capacity for bundling actin filaments (red). Photo: Tobias Goldmann
Usher syndrome is the most common form of combined congenital deaf-blindness in humans and affects 1 in 6,000 of the population. It is a recessive inherited disease that is both clinically and genetically heterogeneous. In the most severe cases, patients are born deaf and begin to suffer from a degeneration of the retina in puberty, ultimately resulting in complete blindness. These patients experience major problems in their day-to-day life. While hearing loss can be compensated for with hearing aids and cochlea implants, it has not proven possible to develop a treatment for the associated sight loss to date. Researchers at Johannes Gutenberg University Mainz (JGU) in Germany have now developed a new treatment approach to this disease.
In previously conducted research into this subject, the research team headed by Professor Uwe Wolfrum of the Institute of Zoology at Mainz University had already gained insight into of the fundamental molecular processes and mechanisms causing this debilitating syndrome. Using the results of this successful basic research, the Usher treatment team in Mainz headed by Dr Kerstin Nagel-Wolfrum has now evaluated potential ocular treatment options. Their attention was focused on a mutation identified in a specific German family known to develop the most severe form of Usher syndrome. This mutation is a so-called nonsense mutation in the USH1C gene, which leads to the generation of a stop signal in a DNA base, resulting in premature termination of protein synthesis.
The Mainz research team has now published its latest work on pharmacogenetic strategies for the treatment of Usher syndrome patients with nonsense mutations in the May edition of the journal Human Gene Therapy. The researchers were able to show that a small molecule known as PTC124 (Ataluren) causes the stop signal in the mutated USH1C gene to be ignored, thus resulting in continuing protein synthesis and the formation of the functional genetic product in cell and organ cultures. In addition to its ability to cause readthrough of stop signals, the active agent PTC124 has also been demonstrated to be highly compatible with murine and human retina cultures. Moreover, the team managed for the first time to demonstrate readthrough of an eye mutation codon in vivo.
"PTC124 is already being tested in clinical trials for its efficacy in treating other diseases involving nonsense mutations, such as cystic fibrosis and Duchenne muscular dystrophy. We therefore hope that this treatment approach will soon be ready for use in Usher syndrome patients," explains Dr Kerstin Nagel-Wolfrum.
Currently putting the finishing touches on his doctoral thesis, Tobias Goldmann is comparing the efficiency of the readthrough rate and the biocompatibility of other molecules that induce the readthrough of nonsense mutations. The focus is particularly on modified aminoglycosides, i.e. derivatives of commercially available and clinically tested antibiotics. These are being designed and synthesized by an Israeli cooperation partner, Professor Timor Bassov of the Haifa Technicon, and have already been successfully used by researchers in Mainz for readthrough of nonsense mutations in Usher genes. In addition to conducting further preclinical studies of the ocular applications of these new substances, the Usher laboratory in Mainz is planning to use this new method of treating this specific form of Usher syndrome in hospital patients as soon as possible.
Goldmann T., Overlack N., Wolfrum U., Nagel-Wolfrum K. (2011): PTC124-Mediated Translational Readthrough of a Nonsense Mutation Causing Usher Syndrome Type 1C. Human Gene Therapy 22:537-547. DOI: 10.1089/hum.2010.067
Goldmann T., Rebibo-Sabbah A., Overlack N., Nudelman I., Belakhov V., Baasov T., Ben-Yosef T., Wolfrum U., Nagel-Wolfrum K. (2010): Beneficial Read-Through of a USH1C Nonsense Mutation by Designed Aminoglycoside NB30 in the Retina. Investigative Ophthalmology & Visual Science 51:6671-80. DOI: 10.1167/iovs.10-5741
Provided by Johannes Gutenberg University Mainz
- Gene therapy involving antibiotics may help patients with Usher syndrome Jun 03, 2008 | not rated yet | 0
- Drug fights cystic fibrosis Feb 05, 2008 | not rated yet | 0
- Study offers clues to beating hearing loss Mar 04, 2009 | not rated yet | 0
- Latest advances in gene therapy for ocular disease are highlighted in Human Gene Therapy May 09, 2011 | not rated yet | 0
- New hope exists in treating inherited disease by suppressing DNA mutations Apr 26, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
University of Minnesota Medical School researchers from the Masonic Cancer Center, University of Minnesota, in partnership with the University's Brain Tumor Program, have developed a new mouse model of malignant peripheral ...
Genetics 16 hours ago | 5 / 5 (1) | 0 |
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 1 |
Informed consent is the backbone of patient care. Genetic testing has long required patient consent and patients have had a "right not to know" the results. However, as 21st century medicine now begins to use the tools of ...
Genetics May 16, 2013 | 5 / 5 (1) | 3 |
Ethicists provide framework supporting new recommendations on reporting incidental findings in gene sequencing
In a paper published in Science Express, a group of experts led by bioethicists in the Center for Medical Ethics and Health Policy at Baylor College of Medicine provide a framework for the new American College of Medical Geneti ...
Genetics May 16, 2013 | not rated yet | 0
The use of genome-wide analysis (GWA), where the entirety of an individual's DNA is examined to look for the genomic mutations or variants which can cause health problems is a massively useful technology for diagnosing disease. ...
Genetics May 16, 2013 | not rated yet | 0
In a remote fishing community in Venezuela, a lone fisherman sits on a cliff overlooking the southern Caribbean Sea. This man –– the lookout –– is responsible for directing his comrades on the water, ...
43 minutes ago | not rated yet | 0 |
A novel approach to obstructing the runaway inflammatory response implicated in some types of asthma has shown promise in a Phase IIa clinical trial, according to U. S. researchers.
37 minutes ago | not rated yet | 0
Authorities are investigating rice mills in southern China following tests that found almost half of the staple grain in one of the country's largest cities was contaminated with a toxic metal.
43 minutes ago | not rated yet | 0
Scientists from Nanyang Technological University (NTU) and Lund University, Sweden, have bioengineered a novel molecule which has been proven to successfully kill tumour cells.
52 minutes ago | not rated yet | 0
Clinical measurement of physical activity appears to be an independent predictor of whether or not patients with chronic obstructive pulmonary disease (COPD) will end up being hospitalized, according to a new study conducted ...
22 minutes ago | not rated yet | 0
Delayed transfer to the intensive care unit (ICU) in hospitalized patients significantly increases the risk of dying in the hospital, according to a new study from researchers in Chicago.
2 minutes ago | not rated yet | 0