{"id":3755,"date":"2012-10-18T12:12:52","date_gmt":"2012-10-18T16:12:52","guid":{"rendered":"https:\/\/blogs.nature.com\/spoonful\/?p=3755"},"modified":"2012-10-26T11:04:41","modified_gmt":"2012-10-26T15:04:41","slug":"sangamo-tries-its-hand-with-zinc-fingers-for-huntingtons","status":"publish","type":"post","link":"https:\/\/blogs.nature.com\/spoonful\/2012\/10\/sangamo-tries-its-hand-with-zinc-fingers-for-huntingtons.html","title":{"rendered":"Sangamo tries its hand with zinc fingers for Huntington\u2019s"},"content":{"rendered":"

<\/strong>NEW ORLEANS \u2014 Sangamo BioSciences<\/a>, the Richmond, California company that has sped ahead with engineered \u2018zinc fingers\u2019, is pointing to these proteins as a powerful tools in treating an ever-increasing list of illnesses. Clinicians at the Glandular Disease Research Clinic in San Antonio, Texas, began testing Sangamo\u2019s first therapeutic in 2006, <\/strong>in individuals with diabetic neuropathy, but this was halted in 2011 <\/strong>at the end of phase 2 clinical trials because there was insufficient evidence of its efficacy. At present, the company is involved in on-going clinical trials of zinc fingers for glioblastoma and HIV. It hopes to eventually add Huntington\u2019s disease to that roster, thanks to encouraging data from tests on cells. But the ease of applying the zinc finger approach to diseases affecting the brain presents a more <\/strong>challenging endeavor.<\/strong><\/p>\n

At the root of Huntington\u2019s disease is a specific type of mutation, called a trinucleotide repeat expansion, in the Huntingtin<\/em> (Htt) gene. The normal Htt gene contains up to 28 copies of the nucleotide sequence CAG, but this expands to more than 40 copies in the disease-causing allele. As a result of the expanded repeat, insoluble clumps of the Huntingtin protein accumulate inside neurons, causing cell death that leads to uncontrollable movements, dementia and, ultimately, death. Patients with between 28 and 35 repeats are unaffected, while those with between 36 and 40 have a form of the disease with reduced penetrance.<\/p>\n

In animal models, reducing mutant Htt protein levels prevents disease progression and reverses some symptoms<\/a>. However, most therapeutic approaches in development lower both versions of the huntingtin protein (the one produced by the normal gene, and the one made by the mutated gene). This has raised concerns about their safety for human use, because the normal protein has important, albeit as yet unknown, cellular function.<\/strong><\/p>\n

To overcome this, Sangamo researchers have developed zinc finger transcriptional repressors that specifically target the mutant Htt allele and block its expression while preserving near-normal expression levels of the normal allele. Zinc fingers are naturally occurring protein segments that recognize and bind to specific DNA sequences, typically regulating the output of a given gene. Using genetic engineering, the Sangamo researchers designed zinc finger proteins containing a DNA-binding site that recognizes the prolonged tricnucleotide repeat found in the mutant Htt gene. They then fused this binding site to a protein domain that recruits other molecules that zip closed the chromosomal region containing the Htt gene with the expanded repeat\u2014thus hindering production of mutated huntingtin protein.<\/p>\n

In a recent experiment in a lab dish, the group added the engineered zinc fingers to fibroblast cells obtained from six people with Huntington\u2019s disease. This lowered production of the mutant protein by more than 90%, while reducing the amount of the normal protein by just 10% or less, the researchers reported at the annual meeting of the Society for Neuroscience<\/a>, held here this week. \u201cThere was very potent discrimination between the mutant and normal alleles in cells from all six patients, even though each contained mutant alleles of different lengths,\u201d explains Phillip Gregory*, chief scientific officer at Sangamo BioSciences. \u201cThe next step is to make that sure they operate at a broad range of doses, and then we need to move into animal studies of efficacy and safety.\u201d<\/p>\n

This is the first attempt to apply the zinc finger approach to Huntington\u2019s disease, and the researchers eventually aim to deliver genes for the zinc finger proteins directly into the brain using adeno-associated viral vectors*, which are already being used to successfully deliver therapeutic genes into the brains of people with Parkinson\u2019s disease in clinical trials<\/strong><\/a>.<\/p>\n

\u201cThis is very promising and exciting work,\u201d says Sarah Tabrizi<\/a>, a professor at the Institute of Neurology in London, <\/strong>who was not involved in the study, \u201cbut it\u2019s still at a very early and exploratory stage, and it\u2019s a big jump going from cells in culture to the human brain.\u201d One challenge is that targeting viral vectors to specified brain areas and then ensuring their proper distribution is difficult, and this is further complicated by the fact that Huntington\u2019s disease begins in deep brain structures before spreading to the cerebral cortex. \u201cDistributing the vector will be a challenge,\u201d Tabrizi says, \u201cbut I don\u2019t think it\u2019s insurmountable.\u201d<\/p>\n

*Correction: The first version of this post incorrectly stated that the chief scientific officer at Sagamo BioSciences is Phillip Gordon, and that Sangamo are planning to use adenovirus vectors to deliver therapeutic genes into the brain.<\/em><\/p>\n","protected":false},"excerpt":{"rendered":"

NEW ORLEANS \u2014 Sangamo BioSciences, the Richmond, California company that has sped ahead with engineered \u2018zinc fingers\u2019, is pointing to these proteins as a powerful tools in treating an ever-increasing list of illnesses. Clinicians at the Glandular Disease Research Clinic in San Antonio, Texas, began testing Sangamo\u2019s first therapeutic in 2006, in individuals with diabetic neuropathy, but this was halted in 2011 at the end of phase 2 clinical trials because there was insufficient evidence of its efficacy. At present, the company is involved in on-going clinical trials of zinc fingers for glioblastoma and HIV. It hopes to eventually add Huntington\u2019s disease to that roster, thanks to encouraging data from tests on cells. But the ease of applying the zinc finger approach to diseases affecting the brain presents a more challenging endeavor.  Read more<\/a> Continue reading →<\/span><\/a><\/p>\n","protected":false},"author":17374,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[],"class_list":["post-3755","post","type-post","status-publish","format-standard","hentry","category-neurosciencemental-health"],"_links":{"self":[{"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/posts\/3755","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/users\/17374"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/comments?post=3755"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/posts\/3755\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/media?parent=3755"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/categories?post=3755"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nature.com\/spoonful\/wp-json\/wp\/v2\/tags?post=3755"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}