Allele-Specific Suppression of Mutant Huntingtin Using Antisense Oligonucleotides: Providing a Therapeutic Option for All Huntington Disease Patients
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{"title"=>"Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: Providing a therapeutic option for all Huntington disease patients", "type"=>"journal", "authors"=>[{"first_name"=>"Niels H.", "last_name"=>"Skotte", "scopus_author_id"=>"54409391300"}, {"first_name"=>"Amber L.", "last_name"=>"Southwell", "scopus_author_id"=>"8160402000"}, {"first_name"=>"Michael E.", "last_name"=>"Østergaard", "scopus_author_id"=>"24923351000"}, {"first_name"=>"Jeffrey B.", "last_name"=>"Carroll", "scopus_author_id"=>"15041752600"}, {"first_name"=>"Simon C.", "last_name"=>"Warby", "scopus_author_id"=>"6507145567"}, {"first_name"=>"Crystal N.", "last_name"=>"Doty", "scopus_author_id"=>"14009857300"}, {"first_name"=>"Eugenia", "last_name"=>"Petoukhov", "scopus_author_id"=>"55962424900"}, {"first_name"=>"Kuljeet", "last_name"=>"Vaid", "scopus_author_id"=>"15836219100"}, {"first_name"=>"Holly", "last_name"=>"Kordasiewicz", "scopus_author_id"=>"14018126000"}, {"first_name"=>"Andrew T.", "last_name"=>"Watt", "scopus_author_id"=>"7103386095"}, {"first_name"=>"Susan M.", "last_name"=>"Freier", "scopus_author_id"=>"7005728264"}, {"first_name"=>"Gene", "last_name"=>"Hung", "scopus_author_id"=>"14056147000"}, {"first_name"=>"Punit P.", "last_name"=>"Seth", "scopus_author_id"=>"7202924626"}, {"first_name"=>"C. Frank", "last_name"=>"Bennett", "scopus_author_id"=>"55665460000"}, {"first_name"=>"Eric E.", "last_name"=>"Swayze", "scopus_author_id"=>"7004515414"}, {"first_name"=>"Michael R.", "last_name"=>"Hayden", "scopus_author_id"=>"55765887300"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84926687571", "pui"=>"608759005", "doi"=>"10.1371/journal.pone.0107434", "sgr"=>"84926687571", "pmid"=>"25207939"}, "id"=>"8998d040-8c89-3d1f-b0bc-d6c7295798bd", "abstract"=>"Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.", "link"=>"http://www.mendeley.com/research/allelespecific-suppression-mutant-huntingtin-using-antisense-oligonucleotides-providing-therapeutic", "reader_count"=>76, "reader_count_by_academic_status"=>{"Unspecified"=>6, "Professor > Associate Professor"=>4, "Researcher"=>17, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>1, "Other"=>6, "Student > Master"=>12, "Student > Bachelor"=>13}, "reader_count_by_user_role"=>{"Unspecified"=>6, "Professor > Associate Professor"=>4, "Researcher"=>17, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>1, "Other"=>6, "Student > Master"=>12, "Student > Bachelor"=>13}, "reader_count_by_subject_area"=>{"Unspecified"=>7, "Biochemistry, Genetics and Molecular Biology"=>14, "Nursing and Health Professions"=>3, "Agricultural and Biological Sciences"=>32, "Medicine and Dentistry"=>5, "Neuroscience"=>10, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>3, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Neuroscience"=>{"Neuroscience"=>10}, "Chemistry"=>{"Chemistry"=>3}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>32}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>14}, "Unspecified"=>{"Unspecified"=>7}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"China"=>1, "Japan"=>1, "South Africa"=>1, "Italy"=>1}, "group_count"=>6}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1669372"], "description"=>"<p>Primary Hu97/18 neurons were treated with ASO at 1–1000 nM for 6, 10, or 15 days. Western blots showing full length spectrin and cleaved spectrin (120 kDa) after 6 (black), 10 (green), and 15 (blue) days of treatment. Spectrin fragment is normalized to calnexin and then to the untreated sample. HTT membranes were reprobed for spectrin. Representative images are shown. Data are presented as mean ± SD with n = 6–12 per data point. The PS backbone is black, MOE and cEt modifications are illustrated by orange and blue, respectively. The SNP is underlined. The red dashed line represents the toxicity threshold.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167053, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g007", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Spectrin_cleavage_after_extended_treatment_duration_/1167053", "title"=>"Spectrin cleavage after extended treatment duration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669357"], "description"=>"<p>(A) ASOs with two different cEt-modified wing motifs (ekek-9-keke and ekk-9-kke) were compared to the parent MOE oligos (5e-9-5e). Primary Hu97/18 neurons were treated with ASO at 1–1000 nM for 6 days. (B) HTT Western blot and quantitations. HTT levels are normalized to the internal loading control calnexin and then to the untreated sample for each allele. (C) Western blots showing full length and cleaved spectrin. Spectrin fragment is normalized to calnexin and then to the untreated sample. Membranes were probed for HTT and reprobed for spectrin. Representative images are shown. n = 6–8 per data point. Data are presented as mean ± SD. Two way ANOVA with Bonferroni post hoc test have been performed and p values are illustrated with *, **, ***, **** for p = 0.05, 0.01, 0.001, and 0.0001. The PS backbone is black, MOE and cEt modifications are illustrated by orange and blue, respectively. The SNP is underlined. The red dashed line represents the toxicity threshold.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167038, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g003", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ASO_screen_at_4_SNPs_using_two_different_cEt_motifs_/1167038", "title"=>"ASO screen at 4 SNPs using two different cEt motifs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669354"], "description"=>"<p>(A) HD-SNPs in the <i>HTT</i> gene: blue = HD-SNPs, pink = previous human fibroblasts screen, grey = Hu97/18 screen; green Rs numbers = SNPs identified as the most RNase-H-active sites (B) ASO development pipeline: The number of targeted SNPs and ASOs tested are shown above and below the column bars, respectively. 50 SNPs are enriched on HD alleles and ASOs targeting 24 of these were previously screened for mHTT mRNA silencing. ASOs targeting 10 SNPs were screened in primary Hu97/18 neurons for HTT protein suppression and tolerability. Then, ASOs with modifications to the wings targeting 4 of these SNPs were screened. Microwalk SAR and 7-base gap SAR was done for oligos targeting SNP Rs7685686. Lastly, higher ASO concentrations and longer treatment durations were tested.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167035, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g001", "stats"=>{"downloads"=>4, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ASO_screening_pipeline_/1167035", "title"=>"ASO screening pipeline.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669366"], "description"=>"<p>(A) Replacing PS-nucleotides with RNase H resistant chemical modifications and shortening the gap from 9 to 7 nucleotides. The top 4 candidates are shown. Primary Hu97/18 neurons were treated with ASO at 1–10000 nM for 6 days. (B) Western blot and quantitation of HTT protein levels. HTT levels are normalized to the internal loading control calnexin and then to the untreated sample for each allele. (C) Western blots showing full length and cleaved spectrin. Spectrin fragment is normalized to calnexin and then to the untreated sample. Membranes were probed for HTT and reprobed for spectrin. Representative images are shown. n = 8–14 per data point at 0–1000 nM and n = 4–6 at 1250–10,000 nM. Data are presented as mean ± SD. Two way ANOVA with Bonferroni post hoc test have been performed and p values are illustrated with *, **, ***, **** for p = 0.05, 0.01, 0.001, and 0.0001. The PS backbone is black, MOE and cEt modifications are illustrated by orange and blue, respectively. The SNP is underlined. The red dashed line represents the toxicity threshold.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167047, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g005", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Shortening_the_gap_to_7_nucleotides_and_evaluation_at_higher_doses_/1167047", "title"=>"Shortening the gap to 7 nucleotides and evaluation at higher doses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669398", "https://ndownloader.figshare.com/files/1669399", "https://ndownloader.figshare.com/files/1669400", "https://ndownloader.figshare.com/files/1669401", "https://ndownloader.figshare.com/files/1669402", "https://ndownloader.figshare.com/files/1669403", "https://ndownloader.figshare.com/files/1669404", "https://ndownloader.figshare.com/files/1669405", "https://ndownloader.figshare.com/files/1669406", "https://ndownloader.figshare.com/files/1669407"], "description"=>"<div><p>Huntington disease (HD) is an inherited, fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The mutant protein causes neuronal dysfunction and degeneration resulting in motor dysfunction, cognitive decline, and psychiatric disturbances. Currently, there is no disease altering treatment, and symptomatic therapy has limited benefit. The pathogenesis of HD is complicated and multiple pathways are compromised. Addressing the problem at its genetic root by suppressing mutant huntingtin expression is a promising therapeutic strategy for HD. We have developed and evaluated antisense oligonucleotides (ASOs) targeting single nucleotide polymorphisms that are significantly enriched on HD alleles (HD-SNPs). We describe our structure-activity relationship studies for ASO design and find that adjusting the SNP position within the gap, chemical modifications of the wings, and shortening the unmodified gap are critical for potent, specific, and well tolerated silencing of mutant huntingtin. Finally, we show that using two distinct ASO drugs targeting the two allelic variants of an HD-SNP could provide a therapeutic option for all persons with HD; allele-specifically for roughly half, and non-specifically for the remainder.</p></div>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167079, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0107434.s001", "https://dx.doi.org/10.1371/journal.pone.0107434.s002", "https://dx.doi.org/10.1371/journal.pone.0107434.s003", "https://dx.doi.org/10.1371/journal.pone.0107434.s004", "https://dx.doi.org/10.1371/journal.pone.0107434.s005", "https://dx.doi.org/10.1371/journal.pone.0107434.s006", "https://dx.doi.org/10.1371/journal.pone.0107434.s007", "https://dx.doi.org/10.1371/journal.pone.0107434.s008", "https://dx.doi.org/10.1371/journal.pone.0107434.s009", "https://dx.doi.org/10.1371/journal.pone.0107434.s010"], "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Allele_Specific_Suppression_of_Mutant_Huntingtin_Using_Antisense_Oligonucleotides_Providing_a_Therapeutic_Option_for_All_Huntington_Disease_Patients_/1167079", "title"=>"Allele-Specific Suppression of Mutant Huntingtin Using Antisense Oligonucleotides: Providing a Therapeutic Option for All Huntington Disease Patients", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669376"], "description"=>"<p>MOE and cEt modifications are annotated by e and k, respectively. The SNP is underlined. Maximal effect at highest dose. IC50, half maximal inhibitory concentration (nM).</p><p>Summary of ASO protein screen in Hu97/18 primary neurons.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167057, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.t001", "stats"=>{"downloads"=>10, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_ASO_protein_screen_in_Hu97_18_primary_neurons_/1167057", "title"=>"Summary of ASO protein screen in Hu97/18 primary neurons.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669375"], "description"=>"<p>(A) The genotypes for the sequenced HD population at rs7685686. Green = heterozygous HD population (rs7685686_A/G, 48.7%, targetable by A-series ASOs and rs7685686_G/A, 3.8%, targetable by X-series ASOs). Blue = homozygous HD population (rs7685686_A/A, 44.9%, targetable by A-series ASOs and rs7685686_G/G, 2.6%, targetable by X-series ASOs). Primary YAC128 neurons were treated with ASO at 16–1000 nM for 6 days. (B) Western blot and quantitation of HTT protein levels. HTT levels are normalized to the internal loading control calnexin and then to the untreated sample for each allele. (C) Western blots showing full length and cleaved spectrin. Spectrin fragment is normalized to calnexin and then to the untreated sample. Membranes were probed for HTT and reprobed for spectrin. Representative images are shown. n = 8–12 per data point. Data are presented as mean ± SD. Two way ANOVA with Bonferroni post hoc test have been performed and p values are illustrated with *, **, ***, **** for p = 0.05, 0.01, 0.001, and 0.0001. The PS backbone is represented by black. MOE and cEt modifications are illustrated by orange and blue, respectively. The SNP is underlined. The red dashed line represents the toxicity threshold.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167056, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g008", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Targeting_two_variants_of_a_single_HD_SNP_to_provide_a_therapeutic_option_to_all_HD_patients_/1167056", "title"=>"Targeting two variants of a single HD-SNP to provide a therapeutic option to all HD patients.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669355"], "description"=>"<p>Primary Hu97/18 neurons were treated with 5e-9-5e ASOs targeted to 10 HD-SNPs at 6–1000 nM for 6 days. (A) HTT Western blots and quantitation for the 4 SNPs with the greatest activity. HTT levels are normalized to the internal loading control calnexin and then to the untreated sample for each allele. (B) Western blots showing full length and cleaved spectrin for the 4 ASOs. Spectrin fragment is normalized to calnexin and then to the untreated sample. Membranes were probed for HTT and reprobed for spectrin. Representative images are shown. n = 4–8 per data point. Data are presented as mean ± SD. Two way ANOVA with Bonferroni post hoc test have been performed and p values are illustrated with *, **, ***, **** for p = 0.05, 0.01, 0.001, and 0.0001. The PS backbone is black and MOE modifications are illustrated by orange. The SNP is underlined. The red dashed line represents the toxicity threshold.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167036, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Selection_of_the_best_SNP_targets_/1167036", "title"=>"Selection of the best SNP targets.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669369"], "description"=>"<p>Primary Hu97/18 neurons were treated with ASO at 1–1000 nM for 6, 10, or 15 days. Western blot and quantitation of HTT protein levels. HTT levels are normalized to the internal loading control calnexin and then to the untreated sample for each allele. Representative images are shown. HTT protein levels (wtHTT = solid line, mHTT = dotted line) at day 6 (black), 10 (green), and 15 (blue). Data are presented as mean ± SD. n = 6–12 per data point. The IC<sub>50</sub> values were compared using the extra-sum-of-squares F test and the F distribution and degrees of freedom F (DFn, DFd) and the associated p-values have been calculated. A38: day 6 vs. 10 F(1,106) = 7.254, P<0.0082; day 6 vs. 15 F(1,109) = 51.51, P<0.0001; day 10 vs. 15 F(1,99) = 18.88, P<0.0001; A39: IC<sub>50,mHTT</sub> 38>17>10; day 6 vs. 10 F(1,115) = 13.94, P<0.0003; day 6 vs. 15 F(1,98) = 25.06, P<0.0001; day 10 vs. 15 F(1,21) = 5.625, P<0.0193); A40: IC<sub>50,mHTT</sub> 122>53>18, day 6 vs. 10 F(1,67) = 6.030, P<0.0167; day 6 vs. 15 F(1,58) = 30.25, P<0.0001; day 10 vs. 15 F(1,61) = 12.68, P<0.0007); A41: IC<sub>50,mHTT</sub> 45>8>6; day 6 vs. 10 F(1,85) = 66.19, P<0.0001; day 6 vs. 15 F(1,76) = 47.82, P<0.0001; day 10 vs. 15 F(1,79) = 1.258, P<0.2655). The PS backbone is black, MOE and cEt modifications are illustrated by orange and blue, respectively. The SNP is underlined.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167050, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g006", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Increased_potency_with_extended_treatment_duration_/1167050", "title"=>"Increased potency with extended treatment duration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1669361"], "description"=>"<p>(A, B) Diagram of microwalk ASOs and HTT mRNA silencing in primary human HD fibroblasts. (A) Starting from A3, we moved one cEt modification to the 5′ wing (ekkk-9-ke) and moved the SNP site from position 4 to 14 (B) Similarly, we moved one cEt modification to the 3′ wing (ek-9-kkke) and moved the SNP site from position 2 to 12. mHTT and wtHTT mRNA were normalized to total RNA and then to the untreated sample. n = 2 per data point. A subset of ASOs from preliminary fibroblast screen marked by #, were evaluated in primary Hu97/18 neurons at 4–1000 nM for 6 days. (C) Western blots of HTT protein and quantitations. HTT levels are normalized to the internal loading control calnexin and then to the untreated sample for each allele. (D) Western blots showing full length and cleaved spectrin. Spectrin fragment is normalized to calnexin and then to the untreated sample. Membranes were probed for HTT and reprobed for spectrin. Representative images are shown. n = 6–10 per data point. Data are presented as mean ± SD. Two way ANOVA with Bonferroni post hoc test have been performed and p values are illustrated with *, **, ***, **** for p = 0.05, 0.01, 0.001, and 0.0001. The PS backbone is black, MOE and cEt modifications are illustrated by orange and blue, respectively. The SNP is underlined. The red dashed line represents the toxicity threshold.</p>", "links"=>[], "tags"=>["chemical modifications", "Huntington Disease Patients Huntington disease", "Allelic variants", "Antisense Oligonucleotides", "cag", "ASO design", "HD alleles", "motor dysfunction", "SNP position", "ASO drugs", "huntingtin expression", "gap", "huntingtin gene", "Mutant Huntingtin", "protein causes", "neurodegenerative disorder", "nucleotide polymorphisms", "Therapeutic Option"], "article_id"=>1167041, "categories"=>["Biological Sciences"], "users"=>["Niels H. Skotte", "Amber L. Southwell", "Michael E. Østergaard", "Jeffrey B. Carroll", "Simon C. Warby", "Crystal N. Doty", "Eugenia Petoukhov", "Kuljeet Vaid", "Holly Kordasiewicz", "Andrew T. Watt", "Susan M. Freier", "Gene Hung", "Punit P. Seth", "C. Frank Bennett", "Eric E. Swayze", "Michael R. Hayden"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0107434.g004", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Microwalk_of_the_SNP_position_within_the_gap_/1167041", "title"=>"Microwalk of the SNP position within the gap.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-10 03:08:37"}

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