DNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo.
Administration, Intravenous
Adoptive Transfer
Animals
Demyelinating Diseases
/ genetics
Encephalomyelitis, Autoimmune, Experimental
/ genetics
Endocytosis
/ drug effects
Female
Gene Expression Regulation
Gene Silencing
Graft vs Host Disease
/ genetics
Humans
Integrin alpha4
/ genetics
Jurkat Cells
Lymphocytes
/ metabolism
Male
Mice, Inbred C57BL
Nucleic Acid Heteroduplexes
/ administration & dosage
Oligonucleotides
/ administration & dosage
RNA
/ metabolism
RNA, Long Noncoding
/ metabolism
RNA, Messenger
/ genetics
Spinal Cord
/ pathology
Tissue Distribution
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 12 2021
22 12 2021
Historique:
received:
28
03
2020
accepted:
19
10
2021
entrez:
23
12
2021
pubmed:
24
12
2021
medline:
12
1
2022
Statut:
epublish
Résumé
Manipulating lymphocyte functions with gene silencing approaches is promising for treating autoimmunity, inflammation, and cancer. Although oligonucleotide therapy has been proven to be successful in treating several conditions, efficient in vivo delivery of oligonucleotide to lymphocyte populations remains a challenge. Here, we demonstrate that intravenous injection of a heteroduplex oligonucleotide (HDO), comprised of an antisense oligonucleotide (ASO) and its complementary RNA conjugated to α-tocopherol, silences lymphocyte endogenous gene expression with higher potency, efficacy, and longer retention time than ASOs. Importantly, reduction of Itga4 by HDO ameliorates symptoms in both adoptive transfer and active experimental autoimmune encephalomyelitis models. Our findings reveal the advantages of HDO with enhanced gene knockdown effect and different delivery mechanisms compared with ASO. Thus, regulation of lymphocyte functions by HDO is a potential therapeutic option for immune-mediated diseases.
Identifiants
pubmed: 34937876
doi: 10.1038/s41467-021-26902-8
pii: 10.1038/s41467-021-26902-8
pmc: PMC8695577
doi:
Substances chimiques
Malat1 long non-coding RNA, mouse
0
Nucleic Acid Heteroduplexes
0
Oligonucleotides
0
RNA, Long Noncoding
0
RNA, Messenger
0
Integrin alpha4
143198-26-9
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7344Informations de copyright
© 2021. The Author(s).
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