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Predictive markers useful in the treatment of fragile X syndrome (FXS)

An X chromosome and syndrome technology, applied in the field of individualized treatment, can solve problems such as limited efficacy and adverse side effects

Inactive Publication Date: 2013-01-09
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drugs are all abandoned due to their limited efficacy and possible adverse side effects

Method used

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  • Predictive markers useful in the treatment of fragile X syndrome (FXS)
  • Predictive markers useful in the treatment of fragile X syndrome (FXS)
  • Predictive markers useful in the treatment of fragile X syndrome (FXS)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0685] Example 1: Setting up a study to identify whether there is a fraction of patient

[0686] The embodiment of the present invention is used as a mGluR5 antagonist (-)-(3aR, 4S, 7aR)

[0687] - A follow-up study of a clinical trial whether methyl 4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylate could provide beneficial treatment to individuals with FXS. This study was established to identify whether there is a subset of patients who respond to treatment with (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylate methyl ester. In an attempt to identify the subset of patients who respond to treatment with (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylate, a study To explore the relationship between FMR1 methylation / mRNA expression and (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylate efficacy in this study relationship between.

[0688] Clinical samples: Of the 30 patients who completed the cl...

Embodiment 2

[0730] Example 2: Restriction enzyme digestion based on Taqman probes for determining FMR1 promoter methylation after real-time PCR detection

[0731] Clinical samples: Of the 26 genomic DNA purified from patients who consented to the pharmacogenetic / pharmacogenomic assessment in Example 1, 12 had sufficient quantities for analysis by probe-based methylation assays.

[0732] Probe-based methylation detection:

[0733] The assay is based on the MethylScreen technology from Orion Genomics (St. Louis, MO). However, it combines methyl-selective restriction enzyme DNA treatment with TaqMan hydrolysis probe-based real-time PCR. Briefly, to assess the methylation status of the FMR1 promoter region, genomic DNA purified from EDTA anticoagulant blood was digested independently and consistently with McrBC and Hhal from NEB (Ipswich, MA) according to the manufacturer's instructions. , resulting in the following four conditions: 1) No enzyme digestion; 2) McrBC digestion; 3) HhaI digest...

Embodiment 3

[0735] Example 3: FMRP assay using time-lapse fluorescence resonance energy transfer (TR-FRET) immunodetection

[0736] The following antibodies were used for TR-FRET immunoassay: F4055 (Sigma, RTGKDRNQKKEKPDSVDG (SEQ ID NO: 7)); 2160 (Millipore; ITVAFENNWQPDRQIPFHD; SEQ ID NO: 8) and H00002332-M03 (Arnold Abnova; ATKDTFHKIKLDVPEDLRQMCAKEAAHKDFKKAVGAFSVTYDPENYQLVI; (SEQ ID NO: 9)).

[0737] Temperature-dependent signaling kinetics of human FMRP protein detection by F4055-H00002332-M03 antibody combination

[0738] HEK293T cells were transiently transfected with eGFP plastids (mock) or human FMRP plastids (transfected with FMRP). Cells were lysed in M-PER (Pierce) lysis buffer, 150 nM NaCl and protease inhibitors. 1 μg of total protein (5 μl) and 1 μl of antibody detection buffer were loaded into each low volume 384 well. The results are shown in figure 2 middle.

[0739] Temperature-dependent signaling kinetics of human FMRP protein detection by MAB2160-F4055 antibody co...

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Abstract

The invention is directed to the use of biomarkers to determine responsiveness of an individual with Fragile X Syndrome (FXS) to treatment with an mGluR5 antagonist.

Description

technical field [0001] The present invention relates to an individualized treatment method. In particular, the invention relates to predicting whether an individual with Fragile X Syndrome will respond clinically to treatment with a particular therapeutic agent. Background technique [0002] Fragile X syndrome (FXS) is the most common cause of inherited mental retardation, with a worldwide incidence of 1 / 4000 males and 1 / 8000 females. The incidence of FXS is 10 to 20 times higher than other X-linked mental retardation. FXS is a monogenic disorder primarily caused by hypermethylation and silent CGG repeat expansion of the fragile X mental retardation 1 (FMR1) gene. The absence of FMR1 protein (FMRP) may result in overstimulation of protein synthesis mediated by metabotropic glutamate receptor 5 (mGluR5) signaling and thus lead to phenotypic diversity in FXS. Antagonists of mGluR5 may reduce mGluR5 signaling and correct defects caused by the absence of Fragile X mental reta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q2600/154C12Q2600/158C12Q2600/106C12Q1/6883G01N33/5308
Inventor B·戈麦斯-曼斯拉Y·何D·约翰斯J·迈耶C·保丁
Owner NOVARTIS AG