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trofinetide  (MedChemExpress)
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MedChemExpress trofinetide
a, Network model for causality-aware discovery (nemoCAD) combines a directed gene-gene and drug-gene interaction network extracted from CTD, TRRUST, and KEGG databases with interaction probabilities inferred from single gene and drug perturbations in LINCS. Transcriptome data from any disease model or patient and corresponding control are used to identify the relevant subnetwork and disease-specific “node weights” that account for probabilities of up-/down-regulation of a gene. A drug-gene interaction probability matrix, inferred from LINCS, is computationally screened against the disease-specific subnetwork to identify compounds that significantly interact with the subnetwork and are ranked by their predicted ability to restore the disease transcriptome back to a healthy state based on single gene and gene network signatures. Downstream analyses can be performed on the resulting gene-gene interaction subnetwork by interrogating the underlying subnetwork structure to find control nodes and other network metrics. Additionally, the chemical structures of the predicted drugs can be clustered by structural similarity based on SMILES notation and annotated protein targets and pathways from DrugBank data. b , Seizure scores for wildtype tadpoles with vehicle alone (WT), MeCP2 knockdown tadpoles (MeCP2 KD), and MeCP2 KD animals treated with indicated doses of <t>trofinetide</t> (Tro), vorinostat (Vor), or ivermectin (Ive) for 0 to 8 days duration starting one week post-fertilization (scale bar at right indicates mean seizure score). c , Graphs showing relative effects on seizure score over 10 days of treatment in MeCP2 KD tadpoles of vehicle and 25 μM vorinostat (Vor) versus 70 μg/mL trofinetide (Tro), a clinical-stage drug with demonstrated efficacy (tadpoles per condition and timepoint: N = 12 Vor and Vehicle, N = 8 Tro; error bars indicate s.d.; ANOVA P = 0.028 Vehicle-treated MeCP2 KD tadpoles did not survive past day 3 of the treatment period in one study and past day 6 in a second study. Immunofluorescence micrographs ( d ) and graphs quantifying cilia orientation ( e ) and length ( f ) showing that abnormalities due to MeCP2 knockdown were restored by treatment with vorinostat (magenta-yellow colormap of fluorescence intensity, cilia stained for tubulin; ****, P < 0.0001) Graph ( g ) and immunofluorescence micrographs ( h ) showing levels of hyperacetylated α-tubulin in the GI tract of control versus Rett tadpoles in the absence or presence of 25 μM vorinostat (Vor). i , Graph showing that the % of ib4+ cells in the GI tract of tadpoles shown in g,h is increased in Rett tadpoles, which is indicative of inflammation and heightened pain response, and that this can be rescued by vorinostat treatment.
Trofinetide, supplied by MedChemExpress, used in various techniques. Bioz Stars score: 94/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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a, Network model for causality-aware discovery (nemoCAD) combines a directed gene-gene and drug-gene interaction network extracted from CTD, TRRUST, and KEGG databases with interaction probabilities inferred from single gene and drug perturbations in LINCS. Transcriptome data from any disease model or patient and corresponding control are used to identify the relevant subnetwork and disease-specific “node weights” that account for probabilities of up-/down-regulation of a gene. A drug-gene interaction probability matrix, inferred from LINCS, is computationally screened against the disease-specific subnetwork to identify compounds that significantly interact with the subnetwork and are ranked by their predicted ability to restore the disease transcriptome back to a healthy state based on single gene and gene network signatures. Downstream analyses can be performed on the resulting gene-gene interaction subnetwork by interrogating the underlying subnetwork structure to find control nodes and other network metrics. Additionally, the chemical structures of the predicted drugs can be clustered by structural similarity based on SMILES notation and annotated protein targets and pathways from DrugBank data. b , Seizure scores for wildtype tadpoles with vehicle alone (WT), MeCP2 knockdown tadpoles (MeCP2 KD), and MeCP2 KD animals treated with indicated doses of trofinetide (Tro), vorinostat (Vor), or ivermectin (Ive) for 0 to 8 days duration starting one week post-fertilization (scale bar at right indicates mean seizure score). c , Graphs showing relative effects on seizure score over 10 days of treatment in MeCP2 KD tadpoles of vehicle and 25 μM vorinostat (Vor) versus 70 μg/mL trofinetide (Tro), a clinical-stage drug with demonstrated efficacy (tadpoles per condition and timepoint: N = 12 Vor and Vehicle, N = 8 Tro; error bars indicate s.d.; ANOVA P = 0.028 Vehicle-treated MeCP2 KD tadpoles did not survive past day 3 of the treatment period in one study and past day 6 in a second study. Immunofluorescence micrographs ( d ) and graphs quantifying cilia orientation ( e ) and length ( f ) showing that abnormalities due to MeCP2 knockdown were restored by treatment with vorinostat (magenta-yellow colormap of fluorescence intensity, cilia stained for tubulin; ****, P < 0.0001) Graph ( g ) and immunofluorescence micrographs ( h ) showing levels of hyperacetylated α-tubulin in the GI tract of control versus Rett tadpoles in the absence or presence of 25 μM vorinostat (Vor). i , Graph showing that the % of ib4+ cells in the GI tract of tadpoles shown in g,h is increased in Rett tadpoles, which is indicative of inflammation and heightened pain response, and that this can be rescued by vorinostat treatment.

Journal: bioRxiv

Article Title: Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling

doi: 10.1101/2022.03.20.485056

Figure Lengend Snippet: a, Network model for causality-aware discovery (nemoCAD) combines a directed gene-gene and drug-gene interaction network extracted from CTD, TRRUST, and KEGG databases with interaction probabilities inferred from single gene and drug perturbations in LINCS. Transcriptome data from any disease model or patient and corresponding control are used to identify the relevant subnetwork and disease-specific “node weights” that account for probabilities of up-/down-regulation of a gene. A drug-gene interaction probability matrix, inferred from LINCS, is computationally screened against the disease-specific subnetwork to identify compounds that significantly interact with the subnetwork and are ranked by their predicted ability to restore the disease transcriptome back to a healthy state based on single gene and gene network signatures. Downstream analyses can be performed on the resulting gene-gene interaction subnetwork by interrogating the underlying subnetwork structure to find control nodes and other network metrics. Additionally, the chemical structures of the predicted drugs can be clustered by structural similarity based on SMILES notation and annotated protein targets and pathways from DrugBank data. b , Seizure scores for wildtype tadpoles with vehicle alone (WT), MeCP2 knockdown tadpoles (MeCP2 KD), and MeCP2 KD animals treated with indicated doses of trofinetide (Tro), vorinostat (Vor), or ivermectin (Ive) for 0 to 8 days duration starting one week post-fertilization (scale bar at right indicates mean seizure score). c , Graphs showing relative effects on seizure score over 10 days of treatment in MeCP2 KD tadpoles of vehicle and 25 μM vorinostat (Vor) versus 70 μg/mL trofinetide (Tro), a clinical-stage drug with demonstrated efficacy (tadpoles per condition and timepoint: N = 12 Vor and Vehicle, N = 8 Tro; error bars indicate s.d.; ANOVA P = 0.028 Vehicle-treated MeCP2 KD tadpoles did not survive past day 3 of the treatment period in one study and past day 6 in a second study. Immunofluorescence micrographs ( d ) and graphs quantifying cilia orientation ( e ) and length ( f ) showing that abnormalities due to MeCP2 knockdown were restored by treatment with vorinostat (magenta-yellow colormap of fluorescence intensity, cilia stained for tubulin; ****, P < 0.0001) Graph ( g ) and immunofluorescence micrographs ( h ) showing levels of hyperacetylated α-tubulin in the GI tract of control versus Rett tadpoles in the absence or presence of 25 μM vorinostat (Vor). i , Graph showing that the % of ib4+ cells in the GI tract of tadpoles shown in g,h is increased in Rett tadpoles, which is indicative of inflammation and heightened pain response, and that this can be rescued by vorinostat treatment.

Article Snippet: Vorinostat and trofinetide for mouse studies were purchased from MedChem Express (Monmouth Junction, NJ, USA).

Techniques: Control, Knockdown, Immunofluorescence, Fluorescence, Staining

a, Bird severity scores measured in MeCP2 −/Y mice treated with vehicle (Rett), trofinetide (100 mg/kg), or vorinostat (50 mg/kg) from day 31 to 51 of age (ANOVA; ****, P < 0.0001). b, elevated-plus maze and, c , Y-novelty maze cognitive tests of MeCP2 −/Y mice comparing vorinostat treatment efficacy to vehicle and trofinetide (ANOVA and Holm-Šídák test; *, P < 0.05; **, P < 0.01). d , diarrhea scored using a 0-3 scale (ANOVA and Holm-Šídák test; ***, P < 0.001; ****, P < 0.0001). Representative images of Sholl analysis of microglial arborization in mouse olfactory ( e ) and the Sholl analysis graph showing the branching profile of microglia ( f ) in control versus Rett mice treated with or without vorinostat (ANOVA and Holm-Šídák test; Control vs. Rett, P = 0.0004; Control vs. Vor, P < 0.0001). g , Levels of indicated cytokines measured in plasma of control mice versus Rett mice with or without treatment with trofinetide (Rett – Tro, 100 mg/kg), vorinostat (Rett – Vor, 50 mg/kg), or vehicle (Rett) for 3 weeks (mean values shown, N = 3, scale at right indicates z-score normalized to wild-type vehicle-treated littermates). The observed baseline inflammatory state in Rett mice agreed with published effects of MeCP2 knockdown .

Journal: bioRxiv

Article Title: Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling

doi: 10.1101/2022.03.20.485056

Figure Lengend Snippet: a, Bird severity scores measured in MeCP2 −/Y mice treated with vehicle (Rett), trofinetide (100 mg/kg), or vorinostat (50 mg/kg) from day 31 to 51 of age (ANOVA; ****, P < 0.0001). b, elevated-plus maze and, c , Y-novelty maze cognitive tests of MeCP2 −/Y mice comparing vorinostat treatment efficacy to vehicle and trofinetide (ANOVA and Holm-Šídák test; *, P < 0.05; **, P < 0.01). d , diarrhea scored using a 0-3 scale (ANOVA and Holm-Šídák test; ***, P < 0.001; ****, P < 0.0001). Representative images of Sholl analysis of microglial arborization in mouse olfactory ( e ) and the Sholl analysis graph showing the branching profile of microglia ( f ) in control versus Rett mice treated with or without vorinostat (ANOVA and Holm-Šídák test; Control vs. Rett, P = 0.0004; Control vs. Vor, P < 0.0001). g , Levels of indicated cytokines measured in plasma of control mice versus Rett mice with or without treatment with trofinetide (Rett – Tro, 100 mg/kg), vorinostat (Rett – Vor, 50 mg/kg), or vehicle (Rett) for 3 weeks (mean values shown, N = 3, scale at right indicates z-score normalized to wild-type vehicle-treated littermates). The observed baseline inflammatory state in Rett mice agreed with published effects of MeCP2 knockdown .

Article Snippet: Vorinostat and trofinetide for mouse studies were purchased from MedChem Express (Monmouth Junction, NJ, USA).

Techniques: Control, Knockdown

a, Bird severity scores measured in MeCP2 −/Y mice treated with vehicle (Rett), trofinetide (100 mg/kg i.p.), or oral vorinostat (50 mg/kg) from day 36, after onset of symptoms, showing significant suppression of symptoms by vorinostat treatment while trofinetide’s effects were indistinguishable from the vehicle control (ANOVA, ****, P < 0.0001). b, elevated-plus maze and, c , Y-novelty maze cognitive tests of MeCP2 −/Y mice comparing vorinostat treatment efficacy to vehicle and trofinetide (ANOVA and Dunnett’s multiple comparison test; *, P < 0.05; **, P < 0.01; ****, P < 0.0001). d , survival curve of animals in this study. e , mobility scored using a 0-2 scale and f , diarrhea scored using a 0-3 scale (ANOVA and Holm-Šídák test; **, P < 0.01 ***, P < 0.001; ****, P < 0.0001). g , breathing difficulty evaluated using a 0-1 score (ANOVA and Dunnett’s multiple comparison test; ***, P < 0.001). Graphs showing levels of hyperacetylated α-tubulin in cells of the multi-ciliated cells in the bronchiolar epithelium of the lung ( h ) and skeletal muscle ( i ) in mice treated as described in a (data are presented as mean ± s.d.; *, P < 0.05; **, P < 0.01; ***, P < 0.001). j , Hematoxylin and eosin (H&E) stained histological sections of colon from the control and drug-treated mice (top row) and immunofluorescent staining for acetylated α-tubulin (middle) and βIII-tubulin (bottom) in these sections. k , Graph showing changes in the βIII-tubulin ratio in drug-treated versus control colon tissues (*, P < 0.05; ****, P < 0.0001).

Journal: bioRxiv

Article Title: Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling

doi: 10.1101/2022.03.20.485056

Figure Lengend Snippet: a, Bird severity scores measured in MeCP2 −/Y mice treated with vehicle (Rett), trofinetide (100 mg/kg i.p.), or oral vorinostat (50 mg/kg) from day 36, after onset of symptoms, showing significant suppression of symptoms by vorinostat treatment while trofinetide’s effects were indistinguishable from the vehicle control (ANOVA, ****, P < 0.0001). b, elevated-plus maze and, c , Y-novelty maze cognitive tests of MeCP2 −/Y mice comparing vorinostat treatment efficacy to vehicle and trofinetide (ANOVA and Dunnett’s multiple comparison test; *, P < 0.05; **, P < 0.01; ****, P < 0.0001). d , survival curve of animals in this study. e , mobility scored using a 0-2 scale and f , diarrhea scored using a 0-3 scale (ANOVA and Holm-Šídák test; **, P < 0.01 ***, P < 0.001; ****, P < 0.0001). g , breathing difficulty evaluated using a 0-1 score (ANOVA and Dunnett’s multiple comparison test; ***, P < 0.001). Graphs showing levels of hyperacetylated α-tubulin in cells of the multi-ciliated cells in the bronchiolar epithelium of the lung ( h ) and skeletal muscle ( i ) in mice treated as described in a (data are presented as mean ± s.d.; *, P < 0.05; **, P < 0.01; ***, P < 0.001). j , Hematoxylin and eosin (H&E) stained histological sections of colon from the control and drug-treated mice (top row) and immunofluorescent staining for acetylated α-tubulin (middle) and βIII-tubulin (bottom) in these sections. k , Graph showing changes in the βIII-tubulin ratio in drug-treated versus control colon tissues (*, P < 0.05; ****, P < 0.0001).

Article Snippet: Vorinostat and trofinetide for mouse studies were purchased from MedChem Express (Monmouth Junction, NJ, USA).

Techniques: Control, Comparison, Staining