Novel nanopolymer RNA therapeutics normalize human diabetic corneal wound healing and epithelial stem cells.

Adenoviridae / physiology Adult Aged Aged, 80 and over Biomarkers / metabolism Cell Survival Cells, Cultured Cornea / drug effects Diabetes Mellitus / pathology Epithelial Cells / drug effects Female Humans Male Middle Aged Nanoparticles / chemistry Oligonucleotides, Antisense / pharmacology Polymers / chemistry RNA / pharmacology Receptors, Cell Surface / metabolism Signal Transduction / drug effects Stem Cells / drug effects Wound Healing / drug effects
Diabetic cornea Gene therapy Limbal stem cells Nanobioconjugate RNA therapeutics Wound healing miRNA

Journal

Nanomedicine : nanotechnology, biology, and medicine
ISSN: 1549-9642
Titre abrégé: Nanomedicine
Pays: United States
ID NLM: 101233142

Informations de publication

Date de publication:
02 2021
Historique:
received: 12 09 2020
revised: 08 10 2020
accepted: 19 10 2020
pubmed: 13 11 2020
medline: 15 12 2021
entrez: 12 11 2020
Statut: ppublish

Résumé

Human diabetic corneas develop delayed wound healing, epithelial stem cell dysfunction, recurrent erosions, and keratitis. Adenoviral gene therapy modulating c-Met, cathepsin F and MMP-10 normalized wound healing and epithelial stem cells in organ-cultured diabetic corneas but showed toxicity in stem cell-enriched cultured limbal epithelial cells (LECs). For a safer treatment, we engineered a novel nanobiopolymer (NBC) that carried antisense oligonucleotide (AON) RNA therapeutics suppressing cathepsin F or MMP-10, and miR-409-3p that inhibits c-Met. NBC was internalized by LECs through transferrin receptor (TfR)-mediated endocytosis, inhibited cathepsin F or MMP-10 and upregulated c-Met. Non-toxic NBC modulating c-Met and cathepsin F accelerated wound healing in diabetic LECs and organ-cultured corneas vs. control NBC. NBC treatment normalized levels of stem cell markers (keratins 15 and 17, ABCG2, and ΔNp63), and signaling mediators (p-EGFR, p-Akt and p-p38). Non-toxic nano RNA therapeutics thus present a safe alternative to viral gene therapy for normalizing diabetic corneal cells.

Identifiants

DOI: 10.1016/j.nano.2020.102332 PMID: 33181273 PMC: PMC8107190
pubmed: 33181273
pii: S1549-9634(20)30186-6
doi: 10.1016/j.nano.2020.102332
pmc: PMC8107190
mid: NIHMS1645286
pii:
doi:

Substances chimiques

Biomarkers 0
Oligonucleotides, Antisense 0
Polymers 0
Receptors, Cell Surface 0
RNA 63231-63-0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

102332

Subventions

Organisme : NEI NIH HHS
ID : R01 EY029829
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY013431
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY025377
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206220
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY031377
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

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Auteurs

Andrei A Kramerov (AA)

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Ruchi Shah (R)

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Hui Ding (H)

Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Eggehard Holler (E)

Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Sue Turjman (S)

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Yaron S Rabinowitz (YS)

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Sean Ghiam (S)

David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Ezra Maguen (E)

American Eye Institute, Los Angeles, CA, USA.

Clive N Svendsen (CN)

Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Mehrnoosh Saghizadeh (M)

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Julia Y Ljubimova (JY)

Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Alexander V Ljubimov (AV)

Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: ljubimov@cshs.org.

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questionsmedicales.fr › Virus › Virus à ADN › Adenoviridae › Novel nanopolymer RNA therapeutics normalize...
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