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EU funded studies on gene therapy and gene-based therapy for ciliopathies

Gene therapy has been used to give mice born without a sense of smell the ability to sniff their surroundings, an international team of researchers say.

EU funded studies on gene therapy and gene-based therapy for ciliopathies. Gene therapy has been used to give mice born without a sense of smell the ability to sniff their surroundings, an international team of researchers say. The mice had a genetic disease which affected microscopic hairs in their body - called cilia - which can detect chemicals in the air. Cilia stick out from many cells in the body. Improper cilia development due to genetic defects can result in a range of disorders called ciliopathies. One symptom can be a lifetime without a sense of smell, called congenital anosmia. The study, published in Nature Medicine looked at mice with a mutation in their Ift88 gene, which meant they struggled to produce cilia and could not smell. The group created a virus which was capable of infecting cells with a working version of the Ift88 gene. This was injected into the nose on three consecutive days. This was able to restore the cilia and a sense of smell. The international team of researchers, of which 3 groups are funded from the SYSCILIA project, part of the ‘Health’ Theme of the EU’s Seventh Framework Programme (FP7), hope their findings will lead to treatments for diseased cilia, which can cause blindness, deafness and kidney disease in people. Prof. Philip Beales from University College London, partner in the in the SYSCILIA project, was involved in the study and interviewed by the BBC. He said: "It is a proof of concept that has shown we can get that gene back into these cells, produce the right protein, produce cilia and function as expected. He said the mice were then able to use their sense of smell to seek out food. However, it is hoped a similar approach could be used for other symptoms of the disorders. Dr. James Battey, director of the US National Institute on Deafness and Other Communications Disorders said: "These results could lead to one of the first therapeutic options for treating people with congenital anosmia. They also set the stage for therapeutic approaches to treating diseases that involve cilia dysfunction in other organ systems, many of which can be fatal if left untreated." Gene addition by viral vectors is a promising strategy for the treatment of hereditary disorders, including retinal diseases. However many genes are frequently alternatively spliced or their coding sequences are too large for any available viral delivery system. Human ciliopathies are often caused by nonsense mutations (30%) resulting in a premature termination codon. Aminoglycosides and PTC124 have tremendous therapeutic potential by promoting read-through of nonsense mutations and thereby generating full length-proteins. Molecular diagnostics allows selection of patients for application of mutation-specific therapies. Such a personalized therapy can be accomplished by administering drugs that induce the translational read-through of nonsense mutations. The group of Prof Uwe Wolfrum, another partner in the SYSCILIA project, compared for the first time the ability of three different translational read-through inducing drugs, NB30, NB54 and PTC124, to induce translational read-through. The attention was focused on a mutation known to develop the most severe form of Usher syndrome, the most common form of inherited deaf-blindness. 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 comparison, published in EMBO Molecular Medicine, emphasizes the potential of NB54 and PTC124 in treating nonsense mutation based retinal disorders.

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