Lipid Nanoparticle Delivery of Chemically Modified NGFR100W mRNA Alleviates Peripheral Neuropathy.
Adv Healthc Mater
; 12(3): e2202127, 2023 Jan.
Article
em En
| MEDLINE
| ID: mdl-36325948
ABSTRACT
Messenger RNA (mRNA) carries genetic instructions to the cell machinery for the transient production of antigens or therapeutic proteins and shows enormous potential in vaccine development, cancer immunotherapy, protein replacement therapy, and genome engineering. Here, the synthesis of chemically modified nerve growth factor mutant (NGFR100W ) mRNA through in vitro transcription is described. After the replacement of the original signal peptide sequence with the Ig Kappa leader sequence, codon-optimized NGFR100W mRNA yielded high secretion of mature NGFR100W , which promotes axon growth in PC12 cells. Using lipid nanoparticle (LNP)-delivery of N1-methylpseudouridine-modified mRNA in mice, NGFR100W -mRNA-LNPs result in the successful expression of NGFR100W protein, which significantly reduces nociceptive activity compared to that of NGFWT . This indicates that NGFR100W derived from exogenous mRNA elicited "painless" neuroprotective activity. Additionally, the therapeutic value of NGFR100W mRNA is established in a paclitaxel-induced peripheral neuropathy model by demonstrating the rapid recovery of intraepidermal nerve fibers. The results show that in vitro-transcribed mRNA has significant flexibility in sequence design and fast in vivo functional validation of target proteins. Furthermore, the results highlight the therapeutic potential of mRNA as a supplement to beneficial proteins for preventing or reversing some chronic medical conditions, such as peripheral neuropathy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças do Sistema Nervoso Periférico
/
Fator de Crescimento Neural
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Adv Healthc Mater
Ano de publicação:
2023
Tipo de documento:
Article