{"id":832,"date":"2025-01-14T19:50:40","date_gmt":"2025-01-14T19:50:40","guid":{"rendered":"http:\/\/cetaitdemain.org\/?p=832"},"modified":"2025-01-14T19:50:40","modified_gmt":"2025-01-14T19:50:40","slug":"although-promising-these-results-suggest-that-more-efficacious-iabs-possibly-directed-against-other-htt-epitopes-coupled-with-more-effective-vectors-could-improve-therapeutic-outcome-even","status":"publish","type":"post","link":"https:\/\/cetaitdemain.org\/?p=832","title":{"rendered":"\ufeffAlthough promising, these results suggest that more efficacious iAbs, possibly directed against other Htt epitopes, coupled with more effective vectors, could improve therapeutic outcome even further"},"content":{"rendered":"

\ufeffAlthough promising, these results suggest that more efficacious iAbs, possibly directed against other Htt epitopes, coupled with more effective vectors, could improve therapeutic outcome even further. Regarding mechanism of iAb action, previous work showed that both Happ1 and VL12. 3 reduce mHtt-induced toxicity and aggregation in cell culture and brain slice models of HD, although by different means (Southwell et al., 2008). and mortality in the R6\/2 HD model. In contrast, Happ1 treatment confers significant beneficial effects in a variety of assays of Procyanidin B1 motor and cognitive deficits. Happ1 also strongly ameliorates the neuropathology found in the lentiviral, R6\/2, N171-82Q, YAC128, and BACHD models of HD. Moreover, Happ1 significantly prolongs the life span of N171-82Q mice. These results indicate that increasing the turnover of mHtt using AAV-Happ1 gene therapy represents a highly Procyanidin B1<\/a> specific and effective treatment in diverse mouse models of HD. Introduction Huntington’s disease (HD) results from the growth of a glutamine repeat in exon 1 (HDx-1) of the huntingtin protein (Htt) (The Huntington’s Disease Collaborative Research Group, 1993). Although the disease-causing mutation is limited to the glutamine repeat, the flanking domains modulate toxicity of the mutant protein (Duennwald et al., 2006). Exon 1 of Htt consists of 17 N-terminal amino acids, the glutamine repeat, two polyproline (polyP) domains separated by a proline-rich (P-rich) domain name [collectively known as the proline-rich region (PRR)], and 13 C-terminal amino acids. The simple, autosomal dominant nature of HD should allow for neuroprotective strategies rather than more complicated restorative strategies. The therapies currently available to HD patients are, however, aimed at symptom management rather than the early stages of the disease. Although HD has a single genetic cause, it has a very complex pathology with detrimental effects on a wide variety of cellular processes. Therefore, it is advantageous in terms of Procyanidin B1 specificity and efficacy to Ptprc<\/a> direct therapy toward the most upstream HD targets including the mutant Htt (mHtt) protein itself. One approach of this type is the use of therapeutic anti-Htt intrabodies (iAbs). Intrabodies are intracellularly expressed, recombinant antibody fragments that provide a powerful therapeutic tool well suited to treatment of protein misfolding neurodegenerative diseases. Intrabodies recognizing different epitopes of the same protein can have vastly different effects (Khoshnan et al., 2002), and they are capable of distinguishing between highly homologous proteins and even different conformations of the same protein (Zhou et al., 2004; Emadi et al., 2007). Intrabodies may also be used to ectopically target proteins to particular cellular compartments using localization sequences (Lecerf et al., 2001; Paganetti et al., 2005). A number of anti-Htt iAbs with therapeutic potential have been generated and characterized. C4, an iAb that recognizes the N terminus of Htt, reduces aggregation and toxicity in cell culture, brain slice, and HD models (Murphy and Messer, 2004; Wolfgang et al., 2005; McLear et al., 2008). This iAb increases turnover of both wild-type (wt) and mutant HDx-1 (mHDx-1) in 293 cells (Miller et al., 2005). MW7 and Happ1, iAbs recognizing the polyP and P-rich domains of Htt, respectively, reduce mHDx-1 aggregation and toxicity in cell culture, brain slice, and models of HD, and increase turnover of mutant but not wtHDx-1 (Khoshnan et al., 2002; Southwell et al., 2008). VL12.3, an iAb that recognizes the N terminus of Htt, potently reduces mHDx-1-induced toxicity in cell culture and brain slice HD models (Colby et al., 2004; Southwell et al., 2008). However, this iAb increases nuclear Htt (Southwell et al., 2008). EM48, an iAb recognizing an epitope C-terminal to the PRR of Htt, preferentially binds mHtt and increases turnover of mHDx-1 in a cell culture model of HD. Adenoviral delivery of EM48 to the brains of R6\/2 and N171-82Q HD model mice improves some aspects of neuropathology as well as motor performance in N171-82Q mice (Wang et al., 2008). This adenoviral delivery strategy is limited to the study of short life span HD models because of the transient transgene expression of the adenoviral vector. While both vectors can infect neurons (depending on the serotype), the adeno-associated computer virus (AAV) vector is usually preferable due to its more stable expression. Due to.<\/p>\n","protected":false},"excerpt":{"rendered":"

\ufeffAlthough promising, these results suggest that more efficacious iAbs, possibly directed against other Htt epitopes, coupled with more effective vectors, could improve therapeutic outcome even further. Regarding mechanism of iAb action, previous work showed that both Happ1 and VL12. 3 reduce mHtt-induced toxicity and aggregation in cell culture and brain slice models of HD, although …<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[46],"tags":[],"class_list":["post-832","post","type-post","status-publish","format-standard","hentry","category-pkc","entry entry-center"],"_links":{"self":[{"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=\/wp\/v2\/posts\/832","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=832"}],"version-history":[{"count":1,"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=\/wp\/v2\/posts\/832\/revisions"}],"predecessor-version":[{"id":833,"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=\/wp\/v2\/posts\/832\/revisions\/833"}],"wp:attachment":[{"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=832"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=832"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cetaitdemain.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=832"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}