Erythroid-Progenitor-Targeted Gene Therapy Using Bifunctional TFR1 Ligand-Peptides in Human Erythropoietic Protoporphyria.
Antigens, CD
/ administration & dosage
Antigens, CD34
/ metabolism
Cell Line
Cell-Penetrating Peptides
/ administration & dosage
Erythroblasts
/ cytology
Erythroid Precursor Cells
/ metabolism
Ferrochelatase
/ genetics
Genetic Therapy
/ methods
Humans
Ligands
Oligonucleotides, Antisense
/ administration & dosage
Protoporphyria, Erythropoietic
/ genetics
Protoporphyrins
/ metabolism
RNA, Messenger
Receptors, Transferrin
/ administration & dosage
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 02 2019
07 02 2019
Historique:
received:
24
06
2018
accepted:
21
12
2018
pubmed:
5
2
2019
medline:
20
11
2019
entrez:
5
2
2019
Statut:
ppublish
Résumé
Erythropoietic protoporphyria (EPP) is a hereditary disease characterized by a deficiency in ferrochelatase (FECH) activity. FECH activity is responsible for the accumulation of protoporphyrin IX (PPIX). Without etiopathogenic treatment, EPP manifests as severe photosensitivity. 95% of affected individuals present a hypomorphic FECH allele trans to a loss-of-function (LOF) FECH mutation, resulting in a reduction in FECH activity in erythroblasts below a critical threshold. The hypomorphic allele promotes the use of a cryptic acceptor splice site, generating an aberrant FECH mRNA, which is responsible for the reduced level of wild-type FECH mRNA and, ultimately, FECH activity. We have previously identified an antisense oligonucleotide (AON), AON-V1 (V1), that redirects splicing to the physiological acceptor site and reduces the accumulation of PPIX. Here, we developed a specific strategy that uses transferrin receptor 1 (TRF1) as a Trojan horse to deliver V1 to erythroid progenitors. We designed a bifunctional peptide (P
Identifiants
pubmed: 30712775
pii: S0002-9297(18)30504-4
doi: 10.1016/j.ajhg.2018.12.021
pmc: PMC6369449
pii:
doi:
Substances chimiques
Antigens, CD
0
Antigens, CD34
0
CD71 antigen
0
Cell-Penetrating Peptides
0
Ligands
0
Oligonucleotides, Antisense
0
Protoporphyrins
0
RNA, Messenger
0
Receptors, Transferrin
0
protoporphyrin IX
C2K325S808
Ferrochelatase
EC 4.99.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
341-347Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Références
Blood. 2014 Dec 4;124(24):3636-45
pubmed: 25339359
Eur J Biochem. 2001 Apr;268(7):2004-12
pubmed: 11277922
N Engl J Med. 2018 Feb 15;378(7):625-635
pubmed: 29443664
Neuromuscul Disord. 2018 Jan;28(1):4-15
pubmed: 29203355
Exp Neurol. 2004 May;187(1):65-75
pubmed: 15081589
Nat Commun. 2018 Feb 19;9(1):723
pubmed: 29459660
Am J Hum Genet. 2014 Apr 3;94(4):611-7
pubmed: 24680888
Proc Natl Acad Sci U S A. 2012 Jan 3;109(1):33-8
pubmed: 22198772
Biochim Biophys Acta. 1982 May 7;687(2):204-10
pubmed: 6284220
J Biol Chem. 1986 Jul 15;261(20):9187-95
pubmed: 3013876
J Clin Neurosci. 2018 Mar;49:1-6
pubmed: 29254734
Nat Mater. 2014 Dec;13(12):1157-64
pubmed: 25282508
Am J Hum Genet. 2006 Jan;78(1):2-14
pubmed: 16385445
Clin Adv Hematol Oncol. 2014 Sep;12(9):606-8
pubmed: 25654482
Lancet. 2010 Mar 13;375(9718):924-37
pubmed: 20226990
Nat Rev Drug Discov. 2018 Feb 28;17(3):156-157
pubmed: 29487392
Nat Genet. 2002 Jan;30(1):27-8
pubmed: 11753383
Biochimie. 1986 Mar;68(3):375-81
pubmed: 2874839
Nat Biotechnol. 2007 Oct;25(10):1165-70
pubmed: 17891134