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Device and method for modulating adma in blood

A technology for blood and blood treatment, which can be used in combination or as a component of a hemodialysis system or in the field of plasma, and can solve problems such as the reduction of ADMA clearance rate

Pending Publication Date: 2022-06-07
ザトラスティーズオブインディアナユニバーシティー
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In disease states where DDAH expression or activity is impaired, ADMA clearance is reduced, leading to its accumulation in tissues and blood

Method used

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  • Device and method for modulating adma in blood
  • Device and method for modulating adma in blood
  • Device and method for modulating adma in blood

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0167] The major route of elimination of ADMA from the body is through the enzymatic action of DDAH. In patients with a wide variety of diseases and conditions (eg renal disease, coronary artery disease, congestive heart failure, hypertension, pulmonary hypertension, and especially end-stage renal failure, surgical patients, trauma patients, intensive care unit patients) Elevated ADMA levels were found in . ADMA levels were also increased in patients with acute kidney injury and contrast-induced kidney injury. Additionally, increased ADMA levels have been reported to be an indicator of cardiovascular-related mortality risk.

[0168] High levels of ADMA and reduced DDAH are found in patients with preeclampsia, which can lead to high blood pressure, kidney damage, reduced fetal growth, and preterm birth. High levels of ADMA are associated with erythropoietin resistance.

[0169] Therefore, there is an urgent need to develop methods for reducing the concentration of ADMA in th...

Embodiment 1

[0205] Recombinant expression and purification of human DDAH

[0206] Methods for cloning DDAH, such as polypeptide and polynucleotide sequences of DDAH and cloning DDAH into host cells, are known to those of ordinary skill in the art. The cDNAs encoding human DDAH 1 and DDAH 2 are set forth in SEQ ID NO: 3 and SEQ ID NO: 4, and the amino acid sequences of human DDAH 1 and DDAH 2 polypeptides are set forth in SEQ ID NO: 1 and SEQ ID NO: 2. The non-human amino acid sequences of DDAH polypeptides are set forth in SEQ ID NOs: 6; 7; 9; 10; 11; Biosynthesis of DDAH polypeptides is accomplished by transforming E. coli with a plasmid comprising the nucleotide sequence of DDAH or a modified DDAH or DDAH analog.

[0207] Wild-type mature DDAH was amplified by PCR from a cDNA synthesis reaction using standard protocols and cloned into pET30 (NcoI-BamHI). The nucleic acid sequence encoding DDAH is subcloned into an expression vector under the constitutive or inducible control of a synt...

Embodiment 2

[0211] E. coli expresses DDAH polypeptides.

[0212] E. coli strain W3110 was used to produce wild-type or modified DDAH. A single Research Cell Bank (RCB) vial was removed from -80°C and thawed at room temperature, then 50 μL was used to inoculate 50 mL seeds supplemented with 50 μg / mL kanamycin sulfate in a 250 mL baffled Erlenmeyer flask Medium (chemically defined medium). Primary seed cultures were grown for approximately 18 hours at 37°C and 250 rpm (1 inch throw). Subculture of primary seed cultures to secondary seed cultures in 500 mL baffled Erlenmeyer flasks containing 100 mL of seed medium supplemented with 50 μg / mL kanamycin sulfate, measured at 600 nm wavelength (OD600) The optical density was 0.05. Secondary seed cultures were grown at 37°C and 250 rpm (1 inch parabola) for approximately 8 hours or when an OD600 of between 2 and 4 was reached.

[0213] Sartorius Biostat B 5-L containers were filled with 2.1-L production medium (chemically defined medium) suppl...

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Abstract

Compositions and methods for metabolic degradation of ADMA are provided. In one embodiment, there is provided a device for reducing ADMA levels in the blood of a patient wherein the device comprises a bioactive dimethylarginine dimethylaminohydrolase (DDAH) polypeptide covalently linked to a solid support. In one embodiment, a method for reducing the level of ADMA in the blood of a patient comprises the step of contacting the blood or blood fraction of the patient with an immobilized bioactive DDAH polypeptide, where contact of the blood of the patient with the DDAH polypeptide results in degradation of ADMA present in the blood of the patient.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to: US Provisional Patent Application No. 62 / 899,763, filed September 13, 2019, the disclosure of which is expressly incorporated herein. [0003] Incorporated by reference to material submitted electronically [0004] The computer readable nucleotide / amino acid sequence listing concurrently filed herein is incorporated by reference in its entirety and is identified as follows: 32 kilobyte ACII (text) file titled "320861SeqListing_ST25.txt" created on September 2020 June 6. Background technique [0005] Asymmetric dimethylarginine (ADMA) is an analog of L-arginine, a naturally occurring metabolic product found in the human circulation. Elevated blood levels of ADMA occur in disease states including hypertension, preeclampsia, diabetes, renal disease, end-stage renal disease (ESRD), or chronic renal and heart failure. High ADMA levels are also generated in patients undergoing heart bypas...

Claims

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Application Information

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IPC IPC(8): A61M1/14C12N9/78A61K38/00A61K38/50A61K45/06
CPCA61K38/00C12N9/78C07K2319/21C12Y305/03018A61M1/3486C12R2001/385C12N11/00C12N11/10A61K47/6921A61P9/12A61M60/113A61M60/36A61K38/50
Inventor 贾伊帕尔·辛格
Owner ザトラスティーズオブインディアナユニバーシティー
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