ライフサイエンスコーパス: off-target

1 ies and selectivity against a panel of other off-targets.

2 activity and gene transcription with minimal off-targets.

3 metabolites possess activity, either on- or off-target?

4 quence compatibilities and the on-target and off-target activities of Cas9 from Streptococcus pyogene

5 Taking into account that also off-target activities of drugs may lead to stimulations

6 ities to specific genomic loci, yet each has off-target activities that are often unpredictable.

7 In the other 6%, MorphEUS pointed to key off-target activities.

8 o determine structural changes that impacted off-target activities.

9 2alpha, they tend to suffer from significant off-target activity and new approaches are needed.

10 nhibits all-trans-RA metabolism with minimal off-target activity and shows therapeutic similarity to

11 reater degree of pHLA selectivity, with less off-target activity in cellular assays.

12 Compound 16 had no significant off-target activity in the protein kinome and only weak

13 However, accurate prediction of CRISPR-Cas9 off-target activity is challenging.

14 reas activity on cytosines is higher and RNA off-target activity is substantially decreased.

15 The decreased off-target activity of AsCas12a (Cpf1) appears to be pri

16 We apply DENT-seq to profile the off-target activity of the Nb.BsmI nicking endonuclease

17 transcriptional data, we found that cellular off-target activity was two to four times more likely to

18 d develop rational approaches for mitigating off-target activity while accounting for the influence o

19 delivering ASOs by free uptake also reduced off-target activity.

20 ty, robust DNA-cleavage activity and minimal off-target activity.

21 ormer fusion protein having particularly low off-target activity.

22 q provides detailed mechanistic insight into off-target activity.

23 ce of ASO chemistry influences the extent of off-target activity.

24 ining of a machine learning model to predict off-target activity.

25 vels of single guide RNA (sgRNA)-independent off-target adenine deamination in genomic DNA and very l

26 in the preterm infant, but evidence suggests off-target adverse effects on the developing cardiovascu

27 f these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash,

28 their therapeutic efficacy and minimize the off-target adverse effects.

29 overcome the pharmacokinetic challenges and off-target adverse effects.

30 epatic first pass metabolism and also limits off-target adverse side effects upon heathy tissues.

31 tent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel.

32 The TMT overlabeling on the off-target amino acid residues serine, threonine, and ty

33 developed a method called GOTI (genome-wide off-target analysis by two-cell embryo injection) to det

34 nscriptional programs in any model, although off-target analysis detected a silent genomic alteration

35 in both in silico and experimental tools for off-target analysis have generated remarkably concordant

36 Future work to improve off-target analysis includes expanding the true off-targ

37 5 and K599 were resequenced, and genome-wide off-target analysis was applied to investigate the edite

38 ng tools for applications in which minimized off-target and high on-target activity are required.

39 engineering tools, but unwanted cleavage at off-target and previously edited sites remains a major c

40 sent were characteristic of Cas9-independent off-targeting and point to TC motifs as activity hotspot

41 ach for suppressing unwanted editing of both off-targets and HDR-corrected sites.

42 ed from sequence, allowing identification of off-targets and prediction of bioactive interactions by

43 DISCOVER-seq (discovery of in situ Cas off-targets and verification by sequencing) is a broadly

44 ee groups: untreated control, VL-saline, and off-target (antennal lobe) procaine.

45 associated with LV mass increase and adverse off-target aortic remodeling.

46 tes improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for beta-cell p

47 Split-FISH reduces off-target background fluorescence, decreases false posi

48 arch and binding behavior as well as role of off-target binding and specificity.

49 TC1 and SA4503 likely have off-target binding to NR2B in vivo.

50 ow frequency of genome-wide Cas9-independent off-target C*G-to-T*A mutation in mouse embryos and in r

51 Their selective inhibition over off-target CAs is expected to produce an anti-NP action

52 This approach assumes that off-target cells cannot incorporate these analogs.

53 maintaining safety by minimizing delivery to off-target cells is a prevalent challenge in the field o

54 understand inflammatory signaling in on- and off-target cells.

55 In the context of SDNs, an off-target change or edit is an unintended, nonspecific

56 SDN-mediated off-target changes can contribute to a small number of a

57 ever, CBEs such as BE3 can cause genome-wide off-target changes via sgRNA-independent DNA deamination

58 Comparing matched genome-wide off-target, chromatin modification and accessibility, an

59 coupling, tumorous vascular activation, and off-target circulation.

60 ic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to

61 Cas9s have increased discrimination against off-target cleavage compared with wild-type Streptococcu

62 Determining the off-target cleavage profile of programmable nucleases is

63 Correspondingly, Cas9 off-target cleavage results in chromosomal losses and he

64 data sets revealed mechanistic insights into off-target cleavage.

65 ut membrane proteome arrays did not identify off-target cytotoxic interactions.

66 heart failure and cancer could have platelet off-target deleterious effects.

67 Current off-target discovery methods work using purified DNA or

68 he basis for improved discrimination against off-target DNA containing important mismatches at the di

69 p to a 45-fold overall reduction in unguided off-target DNA deamination relative to BE4 containing rA

70 ~10-100-fold lower average Cas9-independent off-target DNA editing while maintaining robust on-targe

71 gineering increased rates of dissociation of off-target DNA.

72 ardiovascular complications, possibly due to off-target drug effects.

73 Here, we discuss issues regarding off-targeting during experimental manipulation, and diff

74 tify several sites with previously validated off-target editing activity in cells, our own CRISPR-Cas

75 kably concordant results for sites with high off-target editing activity.

76 an lead to unintended consequences including off-target editing and chromosomal translocations.

77 ticular, we focus on the analysis of on- and off-target editing and CRISPR pooled screen data.

78 iciency, and flexibility, assays to identify off-target editing are becoming more comprehensive and s

79 Off-target editing by these nucleases remains a consider

80 arget editing, and in transcriptome-wide RNA off-target editing can be ameliorated by the introductio

81 g, because even a small number of cells with off-target editing can be detrimental.

82 -target analysis includes expanding the true off-target editing dataset to evaluate new experimental

83 pecially promising for applications in which off-target editing must be minimized.

84 to improve the sensitivity of amplicon-based off-target editing quantification.

85 peutic avenue for genetic diseases, although off-target editing remains a significant safety concern.

86 ew tools developed for identifying potential off-target editing sites and compare the ability of thes

87 rease in Cas9-dependent and -independent DNA off-target editing, and in transcriptome-wide RNA off-ta

88 is able to accurately predict low-frequency off-target editing, presenting a bottleneck in therapeut

89 splays background levels of Cas9-independent off-target editing.

90 s while maintaining minimal Cas9-independent off-target editing.

91 his locus were modified, with no evidence of off-target editing.

92 Within this context, off-target edits in crops present no new safety concerns

93 design genome editing reagents can mitigate off-target edits in plants.

94 se new CBEs eliminated sgRNA-independent DNA off-target edits in rice plants.

95 -G and C-to-T substitutions with minimal RNA off-target edits.

96 mpounds in a blinded study and identified an off-target effect for one compound that was not readily

97 an antifungal drug that inhibits FECH as an off-target effect.

98 We demonstrate dramatically reduced off-target effects (approximately 2- to 93-fold improvem

99 ost CRISPR-Cas systems, however, suffer from off-target effects and unpredictable nonspecific binding

100 overlapping ASO sequences, we conclude that off-target effects are difficult to predict, and the cho

101 canonical isoform, and suggest that on- and off-target effects at isoform-level should be investigat

102 e gold standard assay for assessing the true off-target effects at these candidate sites.

103 hibitors with target selectivity and minimal off-target effects can be challenging.

104 n involves chemotherapy and radiation, where off-target effects can include skeletal muscle decline.

105 focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatmen

106 is approach comes with challenges, including off-target effects due to lack of selectivity.

107 pound, (177)Lu-L1 which demonstrated reduced off-target effects in a xenograft model of prostate canc

108 f many HIs for HIF hydroxylases and possible off-target effects in cellulo are unclear, delaying the

109 erfering RNA treatment caused only low-level off-target effects in KID-KCs, as detected by genome-wid

110 The focal treatment minimizes concerns about off-target effects in other organs and brain areas.

111 ing trauma and cellular injury, and can have off-target effects in which pathways that typically defe

112 These off-target effects include acute organ injury, autoimmun

113 ion agent in kidney transplantation, but its off-target effects make withdrawal desirable.

114 Collectively this indicates that off-target effects may be reduced and/or desirable immun

115 We show that off-target effects of a drug used to inhibit endocytosis

116 nding we leverage to reveal specific on- and off-target effects of both established and candidate the

117 ughput assay for assessing sgRNA-independent off-target effects of CBEs in rice protoplasts.

118 inetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvemen

119 e prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinit

120 They also suggest that off-target effects of DREADD actuators may limit transla

121 applying dose-response metabolomics to find off-target effects of drugs.

122 Off-target effects of systemically administered drugs ha

123 can be demonstrated, and without significant off-target effects of the gene deletion experimental pla

124 We describe profound and unexpected off-target effects of the PPARgamma antagonist 2-chloro-

125 al fibers can maximize efficacy and minimize off-target effects of VNS.

126 Here, we characterize the off-target effects of wild-type (WT) SaCas9 at single-nu

127 ules from dying cancer cells or by mediating off-target effects on immune cell populations.

128 tions are largely or completely explained by off-target effects on L-type VGCCs, which are essential

129 hasone treatment can have direct detrimental off-target effects on the cardiovascular system in the d

130 Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demo

131 rain radiation therapy result in deleterious off-target effects on the normal developing childhood br

132 than in live fingerlings, indicating either off-target effects or pleiotropic effects.

133 ic for the Gaa(c.1826) locus without genomic off-target effects or rearrangements.

134 However, off-target effects remain a major bottleneck that preclu

135 development of drug resistance, and risks of off-target effects remain barriers to prolonged remissio

136 Proton radiotherapy causes less off-target effects than X-rays but is not without effect

137 itro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical

138 non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumou

139 t can be learned about mechanisms of action, off-target effects, and heterogeneous responses.

140 ific drug delivery holds promise in reducing off-target effects, decreasing unwanted toxicities, and

141 brain specificity, brain uptake levels, and off-target effects, driving the search for new and poten

142 ll interfering RNAs (siRNAs) and that reduce off-target effects, immune stimulation, and toxicities o

143 design and optimization of crRNA that limits off-target effects, including the crucial role of an ext

144 ty, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and high

145 To look for off-target effects, we determined the complete exome of

146 apeutics, but their usefulness is limited by off-target effects, which produce alpha-mannosidosis-lik

147 hole-organism physiology and function due to off-target effects.

148 function and the elimination of deleterious off-target effects.

149 e ability of these tools to properly analyze off-target effects.

150 (PAMs), insufficient on-target activity and off-target effects.

151 to enhance its therapeutic potency and avoid off-target effects.

152 nhibition is a viable approach to circumvent off-target effects.

153 inimize inflammation without exerting severe off-target effects.

154 drug targets and enable better prediction of off-target effects.

155 ighly efficient, but also causes significant off-target effects.

156 ed epitranscriptome transcripts with limited off-target effects.

157 orphant phenotypes and those produced due to off-target effects.

158 likely reflects HIF hydroxylase independent off-target effects.

159 ssment of the functional impact of potential off-target effects.

160 the antitumor efficacy and reduce potential off-target effects.

161 ors including depletion onset, duration, and off-target effects.

162 ve and can exhibit toxicity and/or potential off-target effects.

163 lications has been hampered due to undesired off-target effects.

164 is highly programmable and exhibits reduced off-target effects.

165 tly, L-AZM was protective from F-AZM cardiac off-target effects.

166 f the intended target, pharmacokinetics, and off-target effects.

167 against such specific targets, thus limiting off-targeting effects.

168 and suggest that the lack of H3T3ph and the "off-target" effects of 5-ITu can be partially compensate

169 d by CRISPR/Cas9 genome editing, suggesting "off-target" effects.

170 ify new promising (on-target) or unintended (off-target) effects of drugs.

171 However, off-target electrolyte wasting, renal dysfunction, and n

172 , the closest CLC-2 homolog, and exhibits no off-target engagement against a panel of 61 common chann

173 The off-target events caused by the uniformly modified ASOs

174 ting strategies for on-target efficiency and off-target events using personalized iPSC-RPE model syst

175 The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candi

176 Focusing on the off-target evolutionary dynamics may offer novel avenues

177 Our results demonstrate that off-target gastrointestinal populations rapidly respond

178 transcriptome analysis to assess genome-wide off-target gene silencing triggered by the fragments tha

179 sion levels of predicted intended-target and off-target genes using reverse transcription quantitativ

180 Engineered SpCas9s and AsCas12a cleave fewer off-target genomic sites than wild-type (wt) Cas9.

181 V9, reducing the virus' ability to transduce off-target healthy tissue.

182 increase in immunoprecipitation of presumed off-target histone PTMs after inhibitor treatment, a tre

183 applicable approach for unbiased CRISPR-Cas off-target identification in cells and tissues.

184 are important to consider for understanding off-target impacts of IL-2C regimes in experimental mode

185 OVER-seq is capable of finding and measuring off-targets in primary cells and in situ.

186 t the ligands lacked activity at hundreds of off-targets, including several that are associated with

187 nation with MMR appeared safe in relation to off-target infections and was associated with a lower ra

188 accination with live attenuated vaccines and off-target infections are needed.

189 d was associated with a lower rate of severe off-target infections.

190 V cannot be explained solely on the basis of off-target inhibition of mitochondrial DNA polymerase ga

191 Furthermore, 7 exhibited low off-target inhibition of other CYP isozymes.

192 of delayed OP toxicity is thought to involve off-target inhibition of serine proteases, although the

193 olecular variant, but not to other potential off-target inhibitors.

194 gene knock-in rates, systematically reduces off-target insertion and deletion events, maintains or i

195 to treat AIDS patients, likely results from off-target interactions of HIV (aspartyl) protease inhib

196 M with improved pharmacokinetics and reduced off-target interactions relative to our previous series

197 nM; II/IX-SI 56, >4) against CA IX/XII over off-target isoforms.

198 balancing TYK2 potency and selectivity over off-target JAK2 was established.

199 Favorably, 17d exhibited minimum off-target kinase activation.

200 first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP dr

201 elivery of short guide RNAs directed against off-target loci by competition with the on-target guide

202 st-cycle activity but are thought to involve off-target mechanisms outside the apicoplast.

203 as met with significant challenges including off-target mechanisms that induce cytotoxicity independe

204 he electrophile, which increases the risk of off-target modification.

205 CRISPR GUARD reduces off-target mutagenesis while retaining on-target editing

206 s9 system can have some drawbacks, including off-target mutations and mosaicism, particularly when us

207 Yet, nucleases yield off-target mutations and, most pervasively, unpredictabl

208 n fibroblasts do not give rise to detectable off-target mutations at the in vitro-predicted sites.

209 ole-genome sequencing reveals the absence of off-target mutations by Cas9 in the engineered plants.

210 ysis by two-cell embryo injection) to detect off-target mutations by editing one blastomere of two-ce

211 rotein (94.2%), with little to no unintended off-target mutations detected.

212 , level of mosaicism, and evaluate potential off-target mutations utilizing next generation sequencin

213 ency and with minimal formation of indel and off-target mutations, despite the absence of the canonic

214 specific guide RNA (gRNA) binding may induce off-target mutations.

215 ant marker free and does not have detectable off-target mutations.

216 selectivity for Na(V)1.7, examined alongside off-target Na(V)s, compared with HwTx-IV and gHwTx-IV.

217 rrently a pressing need for methods to study off-target nicking activity genome-wide to evaluate the

218 , pulmonary arterial hypertension) and is an off target of anesthetics, antiparkinsonian drugs, and s

219 fficiently and robustly scores the potential off-targeting of all possible candidate CRISPR guide oli

220 and TbetaRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated th

221 inases represent the most potently inhibited off-targets of PARP inhibitors identified to date and sh

222 ulti-omics assessment to determine potential off-targets on the transcriptome and methylome.

223 Morpholinos (MOs) sometimes produce off-target or toxicity-related effects that can be mista

224 However, we inhibited this off-target overlabeling by adding a small-molecule addit

225 Mechanistically, spermine neutralized off-target oxygen free radicals produced by NADPH oxidas

226 conformation, leading to the recognition of off-target peptides sharing little similarity with the c

227 CRs targeting the same Ag recognize the same off-target peptides.

228 through P-gp inhibition and to mitigate the off-target pharmacologic effects that complicate their c

229 -delivery holds promise as a means to reduce off-target pharmacological effects.

230 daptomycin resistance of E. faecium from the off-target population was on average 50% higher than res

231 s of splice-modulating ASOs on 108 potential off-targets predicted on the basis of sequence complemen

232 enty-five of these sites are not reported by off-target prediction software, either because they cont

233 The off-targets present were characteristic of Cas9-independ

234 ir nest, whereas ants from the untreated and off-target procaine groups were well directed and were t

235 but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS,

236 ue is highly specific because we observed no off-target protein destruction.

237 ificant binding to other STATs or additional off-target proteins, confirming their exquisite specific

238 region it is anatomically difficult to avoid off-target radiation exposure to other organs.

239 onic toxicity studies of (225)Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver.

240 However, toxicity linked to off-target reactivity can be minimized by using latent e

241 g to proteins, in part due to concerns about off-target reactivity.

242 pressing two surface antigens while avoiding off-target recognition of single-antigen cells, and thre

243 n efficiently eliminate cancers with reduced off-targets, resistance, and relapse.

244 Prompted by the unexpected detection of an off-target ribosome alteration in the RPS25 knockout, we

245 iant (R33A) previously shown to have reduced off-target RNA and DNA editing activities(5,6).

246 ign rules and develop a comprehensive set of off-target rules to predict and exclude promiscuous guid

247 egFinder can incorporate sgRNA on-target and off-target scoring predictions into its ranking system,

248 the intravenous use of daptomycin generates off-target selection for resistance in transmissible gas

249 BLENDER (blunt end finder), then identifies off-target sequences genome wide.

250 Using systematic measurements of target and off-target sequences under controlled mechanical perturb

251 inase inhibitor, demonstrating that AF is an off-target side effect.

252 ll molecule therapeutics, including reducing off-target side effects and increasing drug potency.

253 ms have been widely explored to reduce their off-target side effects and the medication frequency, wi

254 ainstay of treatment to reduce the risks and off-target side effects associated with systemic therapi

255 ion is resistant to these medications, while off-target side effects lead to dismal patient adherence

256 d to partial-volume effects) and age-related off-target signal (possibly related to iron load).

257 they can be multiplexed to suppress several off-targets simultaneously.

258 Only one predicted off-target site is cleavable in vitro, with negligible d

259 significant effects on activity at ~15.2% of off-target sites analyzed.

260 ther in vitro-based methods and that on- and off-target sites are detectable in gene bodies where sho

261 Here, we report that off-target sites can be shielded from the active Cas9*si

262 at annotate the potential impact of putative off-target sites that lie within regions of functional g

263 , it is necessary to enumerate all potential off-target sites within a given genome that could be ina

264 hould be used together to identify potential off-target sites, and amplicon-based next-generation seq

265 erative targets, while minimizing binding to off-target sites, can translate to improved drug efficac

266 human primary T cells and identified 201,934 off-target sites, enabling the training of a machine lea

267 o enumerate a comprehensive list of putative off-target sites.

268 ge (CRISPR GUARD) as a method for protecting off-targets sites by co-delivery of short guide RNAs dir

269 M and greater than 200-fold selectivity over off-target sodium channel isoforms, Na(V)1.1-1.6 and Na(

270 .1+/-0.4 g sodium in 2 hours with negligible off-target solute removal and overall stable serum elect

271 electrolyte concentrations were stable, and off-target solute removal was negligible.

272 n of large quantities of sodium with limited off-target solute removal.

273 ed mismatches can be used to reduce unwanted off-target splicing events.

274 es such as isolating z-lines from regions of off-target staining that occur along immature stress fib

275 vors release rather than cleavage of a bound off-target substrate only because the cleavage rate is s

276 range, while no affinity was encountered for off-targets, such as hCA I and II.

277 ter molecule that binds more strongly to the off-target than to the target.

278 proved for cancer treatment have significant off-targets that limit their use for autoimmune and infl

279 The compounds were inactive against the off-targets thrombin and trypsin.

280 in the general circulation, thereby avoiding off-target toxic effects.

281 an effort to minimize systemic exposure and off-target toxicities.

282 otoxic effects of Abraxane and to reduce its off-target toxicities.

283 se challenges and innovative means to reduce off-target toxicities.

284 electivity and pharmacokinetics resulting in off-target toxicity and inefficient therapies.

285 Chemotherapy causes off-target toxicity and is often ineffective against sol

286 hat maintain a high cure rate while reducing off-target toxicity are required.

287 mmunotherapy can still introduce significant off-target toxicity, and methods are sought to enable ta

288 ll ablation is limited by their high on- and off-target toxicity, severe side effects, and a narrow t

289 in normal tissue would be expected to lower off-target toxicity.

290 untreated control group, without significant off-target toxicity.

291 in vivo with increased stability and reduced off-target toxicity.

292 herapy agents by tumours and to reduce their off-target toxicity.

293 medulloblastoma cell growth while minimizing off-target toxicity.

294 activates target genes specifically without off-target transcription activation.

295 ewer missense mutations than RESCUE-S at the off-targets transcriptome-wide.

296 GOTI method was designed to detect potential off-target variants of any genome editing tools by the c

297 c background and thus could detect potential off-target variants with high sensitivity.

298 ectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-act

299 DYRK1A activity, to enhance selectivity for off-targets while retaining human beta-cell proliferatio

300 NAs can effectively suppress a wide-range of off-targets with minimal optimization while preserving o