Compositions and methods for cardiac regeneration

A heart tissue and polymer technology, applied in the direction of drug combination, non-active ingredients of polymer compounds, drug delivery, etc., can solve the problems of limited ability of myocardial cell renewal, damage of heart tissue, etc.

Active Publication Date: 2020-03-17
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preventive measures reduce the incidence of heart attacks, but after an initial heart attack, heart tissue is damaged and the main challenge is the limited ability of cardiomyocytes to renew in the adult heart

Method used

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  • Compositions and methods for cardiac regeneration
  • Compositions and methods for cardiac regeneration
  • Compositions and methods for cardiac regeneration

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Preparation and loading of host-guest hydrogels

[0079] Materials Synthesis: Sodium hyaluronate (LifeCore, Chaska, MN) was converted to tetrabutylammonium salt (HA-TBA) by exchange with Dowex-100 resin and neutralization with tetrabutylammonium hydroxide. CD-HA and AD-HA were synthesized as previously described. Briefly, 6-(6-aminohexyl)amino-6-deoxy - Amidation reaction between cyclodextrin and HA-TBA to prepare CD-HA. AD-HA is prepared by combining HA-TBA with 1-adamantaneacetic acid in di-tert-butyl bicarbonate (BOC 2 O) and 4-dimethylaminopyridine (DMAP) in the esterification and synthesis. The product was dialyzed, frozen and lyophilized before use. Use 360MHz 1 H NMR (Bruker) determined the modification of the final product, for CD-HA and AD-HA, the HA modification was about 25% HA disaccharide.

[0080] The miRNA molecules used have the following sequences:

[0081] cel-miR-67 (miR-NC)

[0082] 5'-CGCUCAUUCUGCCGGUUGUUAUG-3' (guide; SEQ ID NO: 14)

[008...

Embodiment 2

[0091] Rhodamine Quenching Test

[0092] To further examine the interaction between cholesterol and CD, we developed a fluorescent binding assay to measure the interaction between cholesterol-modified miR302b / c and CD-HA. The assay is based on the ability of cholesterol to bind to and displace rhodamine B from β-cyclodextrin, resulting in quenching and fluorescence enhancement. Gels were prepared as described in Example 1. Rhodamine B (50 ng / μL) was mixed with varying amounts of CD-HA (0-50 ng / μL) in 200 μL of DI HO to a final concentration to determine the saturation concentration for quenching. For non-quenching assays, rhodamine B (50 g / μL) was mixed with miR-302 mimic (0-5 μM) in a final volume of 200 μL. Emission from 530 to 580 nm was measured on a Tecan Infinite200 plate reader with excitation at 550 nm. The miR-302b-chol affinity to the Rho / CD-HA complex was calculated by fitting the Benesi-Hildebrand equation.

[0093] We found that cholesterol-modified miR-302 mi...

Embodiment 3

[0095] Rheological properties

[0096] To confirm that cholesterol-modified miR-302b and miR-302c mimics (hereafter referred to as miR-302) did not affect the mechanical and erosion behaviors of hydrogels, we performed oscillatory rheological and hydrogel corrosion tests.

[0097]Measurements were performed using an AR2000 stress-controlled rheometer (TA Instruments) equipped with a 20 mm diameter cone-plate geometry, a 42 s cone angle for 59 min and a gap of 27 μm. The rheological properties were checked by time sweep (1.0 Hz; 0.5% strain). For shear recovery experiments, shear thinning was performed at 250% strain and recovery at 0.5% strain, each at 20 Hz.

[0098] Inclusion of miR-302 in the system also did not affect gel erosion at two weeks by the uronic acid assay measuring total hyaluronan degradation (Fig. 1E).

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Abstract

The present disclosure provides microRNA-based therapies using a hydrogel delivery system that provides regenerative approach to myocardial infarction by targeting cardiomyocytes. The hydrogel provides for local and sustained cardiac delivery of microRNAs, such miR-302 mimics that can be used to promote cardiomyocyte proliferation. Also provided are compositions suitable for local and sustained release and methods for intramyocardial gel delivery of a miRNA oligonucleotide.

Description

technical field [0001] The present disclosure relates to methods and compositions for improving cardiac function, particularly following cardiac injury such as myocardial infarction. The composition includes a host-guest hydrogel suitable for sustained release of microRNA over a certain period of time. This microRNA stimulates heart cell proliferation and restores heart function. [0002] Cross References to Related Applications [0003] This application claims priority to US Provisional Application No. 62 / 479,908, filed March 31, 2017, the entire contents of which are hereby incorporated by reference. [0004] Instructions for Electronically Submitted Text Files [0005] The contents of the electronically submitted text file are hereby incorporated by reference in their entirety: Copy of the Sequence Listing in computer readable format (file name: PERA_001_01WO_SeqList_ST25.txt, date of record: March 27, 2018, file size 5KB). Background technique [0006] Heart disease ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7105A61K47/40A61K47/36A61K48/00A61K9/06
CPCA61K9/0019A61K9/06A61K47/34A61K31/7105A61K47/554A61K47/61A61K47/6903A61K47/6951A61P9/04A61K47/36
Inventor E·E·莫里西J·A·伯迪克L·王
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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