Tataxin-sensitive markers for determining efficacy of ataxin replacement therapy

A marker and therapy technology, applied in the direction of determination/testing of microorganisms, microorganisms, measuring devices, etc., can solve the problem of antioxidants and iron chelation not being very effective

Pending Publication Date: 2022-03-01
라리마테라퓨틱스인코포레이티드
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Antioxidants and iron chelation are not very effective and, despite treatment, patients often experience progressive loss of motor control and death, with cardiomyopathy being the leading cause of death

Method used

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  • Tataxin-sensitive markers for determining efficacy of ataxin replacement therapy
  • Tataxin-sensitive markers for determining efficacy of ataxin replacement therapy
  • Tataxin-sensitive markers for determining efficacy of ataxin replacement therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0358] Example 1: Generation of FXN-induced signatures

[0359] FXN fusion protein

[0360] The FXN fusion protein used in this example is a fusion protein comprising TAT-cpp and hFXN linked by a linker at the N-terminus of hFXN (Vyas et al. (2012) Hum. Mol. Genet. 21, 1230-1247) , referred to herein as CTI-1601. The hFXN in the fusion protein is the full-length 210 aa long precursor form of cotaxin, which contains an 80 aa mitochondrial targeting sequence (MTS) at the N-terminus. The full-length hFXN protein (amino acids 1-210) includes the amino acid sequence of SEQ ID NO:1.

[0361]

[0362]

[0363] When the protein is imported into the mitochondrial matrix, it is cleaved at amino acid 81 to generate the mature form of FXN, resulting in mature active FXN of 130 amino acids with a predicted molecular weight of 14.2 kDa (SEQ ID NO: 1).

[0364]

[0365] Full length hFXN (SEQ ID NO: 1 ) includes mature hFXN (SEQ ID NO: 2) and a mitochondrial targeting sequence (...

Embodiment 2

[0409] Example 2: String analysis of FSGM

[0410] This example describes string analysis of the FSGMs shown in Table 2, showing that the protein products of the FSGMs are at least partially biologically connected as a group.

[0411] String analysis was performed using the 85 protein products of the FXN-sensitive genomic markers described in Table 2 using the string database (string-db.org; Szklarczyk et al. (2015) DOI: 10.1093 / nar / gkv1277 and references therein) . string analysis such as figure 1 shown. String analysis represents examples of known and / or predicted protein interactions based on their function. The parameters used to generate clusters in string analysis were: nodes = 85; edges = 97; average node degree = 2.28; average local clustering coefficient = 0.345; expected number of edges = 35; PPI enrichment p-value figure 1 Only some clusters are clearly visible in , while others are not visible in the figure, but these are also listed below in this paper.

[0...

Embodiment 3

[0427] Example 3: Selection of potential FXN target genes after in vitro treatment

[0428] The identification of genes that are inversely regulated by FXN gene ablation followed by FXN protein replacement in vivo suggests that changes in gene expression induced by FXN replacement therapy can be used as an indicator of therapeutic efficacy in patients treated with FXN replacement therapy. Based on this premise, the baseline FXN-induced signature was tested in two in vitro human cell models: Friedreich's ataxia (FDRA)-derived fibroblasts and in

[0429] Musclein protein and mRNA expression in human cell models

[0430] Detection of frataxin in FDRA-derived fibroblasts proteinand mRNA expression. Western blot gels visualized and quantified frataxin protein expression, while frataxin mRNA expression was quantified by qRT-PCR. The results are shown in figure 2 and Table 3.

[0431] figure 2 Fraxin detection in control GM23971 cells and FDRA-derived fibroblasts FAGM03816...

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Abstract

The present disclosure is based, at least in part, on providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), each expression level of which exhibits a positive or negative correlation with an ataxin (FXN) level in a cell. Thus, these FSGMs may be used to determine, assess, and / or monitor the efficacy of FXN replacement therapy in a subject.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application No. 62 / 840,878, filed April 30, 2019, the entirety of which is expressly incorporated herein by reference. [0003] sequence listing [0004] This application contains a Sequence Listing filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 30, 2020, is named 130197-00320_SL.txt and is 8,701 bytes in size. Background technique [0005] Mitochondrial diseases are a group of conditions caused by dysfunctional mitochondria, organelles that store potential energy in the form of adenosine triphosphate (ATP) molecules and are present in every cell of the body except mature red blood cells. [0006] Friedreich's ataxia (FRDA), the most common hereditary ataxia in humans, is regulated by the mitochondrial protein frataxin (FXN), specifically human frataxin (hFXN) caused by lack. FRDA is a rare disease with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6883G01N33/68C07K14/47C07K14/155
CPCC12Q1/6883G01N33/6893C07K14/005C07K14/47C12N2740/16022C12Q2600/158C12Q2600/106C07K2319/00C12Q1/6809C12N2740/16071C12N7/00C12N2740/16033G01N33/53
Inventor J·D·贝图恩
Owner 라리마테라퓨틱스인코포레이티드
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