{"id":259,"date":"2015-07-13T22:08:46","date_gmt":"2015-07-13T22:08:46","guid":{"rendered":"http:\/\/www.kurzweilai.net\/?p=256283"},"modified":"2015-07-15T01:35:13","modified_gmt":"2015-07-15T01:35:13","slug":"gene-therapy-restores-hearing-in-deaf-mice","status":"publish","type":"post","link":"https:\/\/hoo.central12.com\/fugic\/2015\/07\/13\/gene-therapy-restores-hearing-in-deaf-mice\/","title":{"rendered":"Gene therapy restores hearing in deaf mice"},"content":{"rendered":"
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The inverted V\u2019s above are sensory hair bundles in the ear, each containing 50 to 100 microvilli tipped with TMC proteins. Gene therapy restores hearing by providing working copies of those proteins. (credit: Gwenaelle Geleoc & Artur Indzhykulian)<\/p><\/div>\n

Patients with hearing loss will one day have their genome sequenced and their hearing restored by gene therapy, says Jeffrey Holt, PhD<\/a>,\u00a0 a scientist in the\u00a0F.M. Kirby Neurobiology Center<\/a>\u00a0at Boston Children\u2019s Hospital and an\u00a0associate professor of Otolaryngology at Harvard Medical School<\/a>.<\/p>\n

A proof-of-principle study\u00a0published<\/a> by the journal\u00a0Science Translational Medicine<\/em>\u00a0takes a step in that direction, restoring hearing in deaf mice. Clinical trials of gene therapy for humans could be started within 5 to 10 years, Holt believes.<\/p>\n

Holt, with first author Charles Askew and colleagues at\u00a0\u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne<\/a>\u00a0in Switzerland, focused on deafness caused by a gene called\u00a0TMC1<\/em> — one of more than 70 different genes are known to cause deafness when mutated. TMC1<\/em>\u00a0accounts for 4 to 8 percent of genetic deafness, and also encodes a protein that\u2019s critical for hearing by helping to convert sound into electrical signals that travel to the brain<\/a>.<\/p>\n

To deliver the functioning\u00a0TMC1<\/em>\u00a0gene into the ear, the team inserted it into an engineered virus called adeno-associated virus 1, or AAV1, and added a promoter, a genetic sequence that turns the gene on only in certain sensory cells in the cochlea, known as hair cells.<\/p>\n

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“I heard that!” Rasbak\/Wikimedia Commons<\/p><\/div>\n

They then injected the engineered AAV1 into the inner ears of mutant, deaf mice modeling the more common recessive form of\u00a0TMC1<\/em>\u00a0deafness, which causes profound hearing loss in children from a very young age, usually by around 2 years. After the injection, the animals\u2019 sensory hair cells began responding to sound and electrical activity began showing up in the auditory portion of their brainstems.<\/p>\n

How it works<\/h4>\n

Holt\u2019s team showed in 2013 that TMC1 and the related protein TMC2\u00a0are critical for hearing<\/a>, ending a rigorous 30-year search by scientists. Sensory hair cells contain tiny projections called microvilli, each tipped with a channel formed by TMC1 and TMC2 proteins. Arriving sound waves wiggle the microvilli, causing the channels to open. That allows calcium to enter the cell, generating an electrical signal that travels to the brain and ultimately translates to hearing.<\/p>\n

Although the channel is made up of either TMC1 or TMC2, a mutation in the\u00a0TMC1\u00a0<\/em>gene is sufficient to cause deafness. However, Holt\u2019s study also showed that gene therapy with the\u00a0TMC2\u00a0<\/em>gene could compensate for loss of a functional\u00a0TMC1<\/em>, restoring hearing in the recessive deafness model and partial hearing in a mouse model of dominant TMC1 deafness, in which patients gradually go deaf beginning around 10 to 15 years of age.<\/p>\n

\n

Abstract of\u00a0Tmc gene therapy restores auditory function in deaf mice<\/em><\/h4>\n

Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mouse models of genetic deafness. We focused on DFNB7\/11 and DFNA36, which are autosomal recessive and dominant deafnesses, respectively, caused by mutations in transmembrane channel\u2013like 1 (TMC1<\/em>). Mice that carry targeted deletion of\u00a0Tmc1<\/em>\u00a0or a dominant\u00a0Tmc1<\/em>\u00a0point mutation, known as\u00a0Beethoven<\/em>, are good models for human DFNB7\/11 and DFNA36. We screened several adeno-associated viral (AAV) serotypes and promoters and identified AAV2\/1 and the chicken \u03b2-actin (Cba<\/em>) promoter as an efficient combination for driving the expression of exogenous\u00a0Tmc1<\/em>\u00a0in inner hair cells in vivo. Exogenous\u00a0Tmc1<\/em>\u00a0or its closely related ortholog,\u00a0Tmc2<\/em>, were capable of restoring sensory transduction, auditory brainstem responses, and acoustic startle reflexes in otherwise deaf mice, suggesting that gene augmentation with\u00a0Tmc1<\/em>\u00a0or\u00a0Tmc2<\/em>\u00a0is well suited for further development as a strategy for restoration of auditory function in deaf patients who carry\u00a0TMC1<\/em>\u00a0mutations.<\/p>\n","protected":false},"excerpt":{"rendered":"

Patients with hearing loss will one day have their genome sequenced and their hearing restored by gene therapy, says Jeffrey Holt, PhD,  a scientist in the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and an associate professor of Otolaryngology at Harvard Medical School. A proof-of-principle study published by the journal Science Translational Medicine takes a step in that direction, restoring […]<\/p>\n","protected":false},"author":13,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[49,56,43],"tags":[],"class_list":["post-259","post","type-post","status-publish","format-standard","hentry","category-cognitive-scienceneuroscience","category-human-enhancement","category-news"],"_links":{"self":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts\/259"}],"collection":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/users\/13"}],"replies":[{"embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/comments?post=259"}],"version-history":[{"count":1,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts\/259\/revisions"}],"predecessor-version":[{"id":260,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/posts\/259\/revisions\/260"}],"wp:attachment":[{"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/media?parent=259"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/categories?post=259"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/hoo.central12.com\/fugic\/wp-json\/wp\/v2\/tags?post=259"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}