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Amino acid compositions and methods for treating cystic fibrosis

A technology of amino acids and free amino acids, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, pharmaceutical formulations, etc., can solve problems such as one or more of a few mutations, single codon loss, etc.

Pending Publication Date: 2021-07-23
UNIV OF FLORIDA RES FOUNDATION INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] While more than 2,000 CFTR mutations have been identified in patients with cystic fibrosis, the vast majority of cystic fibrosis diagnoses present only one or more of a handful of mutations
3 The most common mutation, Phe508del, is a deletion of 3 nucleotides, resulting in the loss of a single codon for the amino acid phenylalanine (three-letter code: Phe, one-letter code: F)
5 There is a clear unmet need for therapies to treat cystic fibrosis, especially for patients carrying the most prevalent CFTR mutation, Phe508del CFTR

Method used

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  • Amino acid compositions and methods for treating cystic fibrosis
  • Amino acid compositions and methods for treating cystic fibrosis
  • Amino acid compositions and methods for treating cystic fibrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0241] Described herein are selected amino acids (AAs) or combinations thereof in formulations capable of stimulating chloride secretion and reducing ENaC activity by increasing CFTR and reducing ENaC expression and activity on the apical membrane. AA formulations were tested in primary human bronchial epithelial cells (HBEC) with the mutation CFTRΔF508. Cells were obtained from CF and non-CF patients. Cells were grown to 80% confluency in Petri dishes before they were transferred into snapwell permeable inserts. Cells were grown to maturity in permeable cell culture supports and differentiated in the air-medium interface for approximately 30 days. Afterwards, study cells in a Uss chamber to measure transepithelial currents and electrical resistance.

[0242] After exposure to selected AA formulations (CF3AA, CF4AA-1 / 2 / 4, CF5AA), CF4AA-3 (negative control), and vehicle (control) in Uss chambers, cultures at the air-liquid interface for 28 to 42 Short-circuit current (Isc) a...

Embodiment 2

[0250] Materials and methods

[0251] Cell model: Fully differentiated primary normal human bronchial epithelial cells (HBEC) and homozygous CFTRΔF508 HBEC (CF cells) were cultured on snapwells at the air-liquid interface for 28 to 40 days.

[0252] Uss chamber: measurement of transepithelial short-circuit current (I sc ), resistance (R) and 22 Na and 36 One-way flux of Cl (J ms &J sm ) and net flux (J net ). Chloride secretion was stimulated with forskolin (FSK, 10 μM apical and basolateral) and the potentiator GLPG1837 (3 μM apical), and with benzamil (6 μM apical) and bumetanide (20 uM apical and basolateral) For blocking ENaC and NKCC.

[0253] Statistics: Statistical differences between vehicle and AA formulations were calculated using analysis of variance (OriginPlus 2016). P<0.05 was considered statistically significant.

[0254] Especially with Figure 10 and Figure 11 Additional experimental details pertinent are as follows:

[0255] The effect of C18 and / o...

Embodiment 3

[0272] Background: In patients with cystic fibrosis, the homozygous F508del mutation causes misfolding, defective trafficking, and aberrant gating of the CFTR protein, resulting in decreased chloride secretion, leading to chronic airway inflammation and infection. Combinations of small molecules that correct CFTR misfolding / trafficking (VX809 and VX661) and enhance CFTR gating (VX770) have been approved for the treatment of patients with F508del who have suboptimal drug efficacy and adverse effects. The present inventors compared CF5AA-3 to the efficiency or additive of trafficking-deficient CFTR and increased chloride secretion in primary human bronchial epithelial cells with homozygous F508del (HBEC-F508del) with treatment with VX809 / VX770 or VX661 / VX770 alone. Efficiency is compared.

[0273] Methods: Transepithelial short-circuit currents and transepithelial short-circuit currents were measured in differentiated HBEC-F508del immersed in vehicle (no AA), AA test preparation...

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Abstract

Provided herein are amino acid compositions useful for increasing the translocation of the cystic fibrosis transmembrane conductance (CFTR) protein from the cytoplasm to the plasma membrane, particularly in epithelial cells. Methods for increasing the concentration of CFTR in the plasma membrane, increasing chloride ion transport, and increasing water transport are also provided. These compositions and methods are useful in treating cystic fibrosis in subjects bearing one or more mutations in the CFTR protein. Use of these compositions for the treatment of cystic fibrosis and in the preparation of a medicament for the treatment of cystic fibrosis are also encompassed herein.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application No. 62 / 752,847, filed October 30, 2018, which is incorporated herein by reference for all purposes. [0003] sequence listing [0004] This application contains a Sequence Listing, which is filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 25, 2019, is named 174821-013301PCT_SL.txt and is 25,987 bytes in size. technical field [0005] Described herein are amino acid compositions useful for increasing the translocation of cystic fibrosis transmembrane conductance (CFTR) protein from the cytoplasm to the plasma membrane. Also provided are methods for increasing the concentration of CFTR in the plasma membrane, increasing chloride ion transport, and increasing water transport. The compositions and methods described herein are useful for treating cystic fibrosis in subjects carrying one or more mutat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/198A61K31/401A61P11/00A61P43/00
CPCA61P43/00A61K31/401A61P11/00A61K31/198A61K31/47A61K2300/00A61K45/06
Inventor S·维迪亚萨格A·格罗舍徐晓东林珊珊S·普拉巴卡兰
Owner UNIV OF FLORIDA RES FOUNDATION INC