Modeling neurological disorders and ataxias with cardiac dysfunction using bioengineered heart tissues

A heart tissue, engineering technology, applied in biochemical equipment and methods, microbes, biological tests, etc.

Pending Publication Date: 2020-11-20
NOVOHEART LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, to date, there have been no reports or publications examining or suggesting examination of the systolic or electrophysiological properties of such CMs in multicellular cardiac simulation models

Method used

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  • Modeling neurological disorders and ataxias with cardiac dysfunction using bioengineered heart tissues
  • Modeling neurological disorders and ataxias with cardiac dysfunction using bioengineered heart tissues
  • Modeling neurological disorders and ataxias with cardiac dysfunction using bioengineered heart tissues

Examples

Experimental program
Comparison scheme
Effect test

example 3

[0081] The following examples illustrate embodiments of the present invention. Example 1 discloses the experimental materials and methods disclosed herein are used. Example 2 shown as reprogramming fibroblasts from FRDA patients showed FXN hiPSC reduced level of expression. Example 3 determines the like having hESC-hvCM FXN gene knockdown FXN exhibit reduced expression and decreased systolic function. Example 4 shows deficient hvCTS FXN having the ability to produce a reduced force of contraction. Example 5 discloses the electrophysiological characteristics FXN deficient hvCAS exhibits altered. 6 shows an example save FXN deficiency restore contractile force hvCTS in. Example 7 shows that under baseline conditions and upon treatment with 0.1μM isoproterenol, FXN deficient hvCOC having systolic dysfunction, such as impaired by the stroke volume, stroke volume, cardiac output, and developed pressure as indicated .

example 1

[0083] This example describes the materials and methods used in the experiments disclosed in the Examples herein.

[0084] hPSC culture and differentiation of the CM

[0085] At 37 [deg.] C with 5% CO 2 Under the health hESC (HES2; ESI, NIH Code ESO 2 ) And FRDA patient-specific hiPSC (FRDA (68) and FRDA (03665) cultured on Matrigel (Coming) having mTeSR1 in hESC media (Stem Cell Technologies) is defined by the transcription factor OCT3 / 4, SOX2, KLF4 the culture (Gibco) hESC, L-MYC LIN28 and shRNA interference plus p53 transfection free from nuclear hiPSC (PB02) peripheral blood mononuclear cells having reprogramming Essential 8 medium (Gibco) defined Geltrex. in order to differentiate into cardiomyocytes hPSC the dissociated hPSC in ultralow attachment plates having 1ng / ml bone morphogenetic cell clusters formed overnight mTeSR1 protein 4 (BMP4) and in anaerobic conditions. from day 1 to on day 4, under hypoxic conditions, supplemented with GlutaMAX (Thermo FisherScientific) ...

example 2

[0097] HiPSC from FRDA patients with fibroblasts exhibited reduced FXN expression

[0098] A healthy HESC, a healthy HIPSC, and two FRDA-HIPSC FRDA (68) and FRDA (03665) expressions from two patients were evaluated. Two FRDA-HIPSC systems are equivalent to FXN at the transcriptional level, both more than 50% lower than healthy HESC and HIPSC-based FXN ( figure 1 B). FXN's protein levels are consistent with transcription, relative to health HPSC, FRDA-HIPSC express the lowest level FXN. Compared with HESC compared with FRDA (68) compared to HIPSCS, the difference in expression of two FRDA is statistically significant. figure 1 B).

[0099] Example 3

[0100] Low models from HESC-HVCM-generated gene FXN knockdown model showed reduced FXN expression and contraction

[0101] In order to simulate and study progress in genetically human CM in vitro, the HESC-derived HVCM derived by two LV-SHFXN constructs LV-SHFXN1 and LV-SHFXN2, and transduced as a control in non-targeted LV-SHNT. Comp...

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Abstract

The disclosure provides a system for screening compounds for therapeutic cardiac effects in the cells, tissues and organoids of patients having diseases such as neurological diseases or disorders withsignificant cardiac comorbidities. The system comprises a medical device apparatus that can be suitable for a single-tier screen for cardio-active compounds that comprises a human ventricular cardiacanisotropic sheet (hvCAS) and human ventricular cardiac tissue strip (hvCTS), a two-tier system further comprising human ventricular cardiac organoid chamber (hvCOC), or a three-tier system still further comprising a medical device comprising multiple organoids, which include tissues or organoids of the same or different type (e.g., heart, liver, pancreas, kidney). Another aspect of the disclosure is the methods suitable for use with the systems, comprising screens for identifying compounds having cardiac effects on cells, tissues or organoids of patients having a non-cardiac disease exhibiting a cardiac effect, such as neurological diseases. The methods are further useful in assessing the toxicity of compounds to various cells, tissues or organoids of such patients.

Description

[0001] Cross-reference related application [0002] This application claims priority to US provisional patent application March 28, 2018 filed interests No. 62 / 649,468, which is hereby incorporated herein by reference in a way in. Technical field [0003] The present disclosure relates generally to the field of health and medicine cardiac physiology, and more particularly, to the field of in vitro screening model and on cells from a diseased patient's cardiac function. Background technique [0004] Friedreich's ataxia (Friedreich's ataxia, FRDA) is an inherited neurodegenerative disease, by the first intron of the frataxin (FXN) gene on chromosome 9 mutation, whereby healthy individuals repeat up to 40 times the normal three-guanine nucleotides - adenine - adenine (GAA) sequence will reappear several hundred to a thousand times. Even if a fully functional wild-type protein in FRDA patients FXN intron mutations leading to the expression of FXN significantly reduced compared to n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/50
CPCC12N2740/16043G01N33/5044G01N33/5082C12N5/0657G01N2500/10
Inventor 李登伟K·D·科斯塔
Owner NOVOHEART LTD
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