eprintid: 1555497
rev_number: 33
eprint_status: archive
userid: 608
dir: disk0/01/55/54/97
datestamp: 2017-05-07 03:39:15
lastmod: 2021-12-13 02:57:41
status_changed: 2017-06-23 09:40:32
type: article
metadata_visibility: show
creators_name: Debnath, S
creators_name: Jaako, P
creators_name: Siva, K
creators_name: Rothe, M
creators_name: Chen, J
creators_name: Dahl, M
creators_name: Gaspar, HB
creators_name: Flygare, J
creators_name: Schambach, A
creators_name: Karlsson, S
title: Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia
ispublished: pub
divisions: UCL
divisions: B02
divisions: D13
keywords: Diamond-Blackfan anemia, gene therapy, lentiviral vectors
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
abstract: Diamond-Blackfan anemia is a congenital erythroid hypoplasia and is associated with physical malformations and a predisposition to cancer. Twenty-five percent of patients with Diamond-Blackfan anemia have mutations in a gene encoding ribosomal protein S19 (RPS19). Through overexpression of RPS19 using a lentiviral vector with the spleen focus-forming virus promoter, we demonstrated that the Diamond-Blackfan anemia phenotype can be successfully treated in Rps19-deficient mice. In our present study, we assessed the efficacy of a clinically relevant promoter, the human elongation factor 1α short promoter, with or without the locus control region of the β-globin gene for treatment of RPS19-deficient Diamond-Blackfan anemia. The findings demonstrate that these vectors rescue the proliferation defect and improve erythroid development of transduced RPS19-deficient bone marrow cells. Remarkably, bone marrow failure and severe anemia in Rps19-deficient mice was cured with enforced expression of RPS19 driven by the elongation factor 1α short promoter. We also demonstrate that RPS19-deficient bone marrow cells can be transduced and these cells have the capacity to repopulate bone marrow in long-term reconstituted mice. Our results collectively demonstrate the feasibility to cure RPS19-deficient Diamond-Blackfan anemia using lentiviral vectors with cellular promoters that possess a reduced risk of insertional mutagenesis.
date: 2017-08-02
date_type: published
official_url: http://doi.org/10.1016/j.ymthe.2017.04.002
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1292355
doi: 10.1016/j.ymthe.2017.04.002
pii: S1525-0016(17)30161-2
lyricists_name: Gaspar, Hubert
lyricists_id: HBGAS19
actors_name: Gaspar, Hubert
actors_name: Stacey, Thomas
actors_id: HBGAS19
actors_id: TSSTA20
actors_role: owner
actors_role: impersonator
full_text_status: public
publication: Molecular Therapy
volume: 25
number: 8
pagerange: 1805-1814
event_location: United States
issn: 1525-0024
citation:        Debnath, S;    Jaako, P;    Siva, K;    Rothe, M;    Chen, J;    Dahl, M;    Gaspar, HB;             ... Karlsson, S; + view all <#>        Debnath, S;  Jaako, P;  Siva, K;  Rothe, M;  Chen, J;  Dahl, M;  Gaspar, HB;  Flygare, J;  Schambach, A;  Karlsson, S;   - view fewer <#>    (2017)    Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia.                   Molecular Therapy , 25  (8)   pp. 1805-1814.    10.1016/j.ymthe.2017.04.002 <https://doi.org/10.1016/j.ymthe.2017.04.002>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1555497/1/Gaspar_lentiviral%20vectors.pdf