|
|
Blood, 1 November 2006, Vol. 108, No. 9, pp. 2979-2988.
Prepublished online as a Blood First Edition Paper on July 11, 2006; DOI 10.1182/blood-2006-05-023507.
 Previous Article | Next Article 
Submitted December 28, 2005
Accepted June 20, 2006
Ex vivo gene therapy with lentiviral vectors rescues
adenosine deaminase (ADA)-deficient mice and corrects
their immune and metabolic defects
Alessandra Mortellaro, Raisa Jofra Hernandez, Matteo M Guerrini, Filippo Carlucci, Antonella Tabucchi, Maurilio Ponzoni, Francesca Sanvito, Claudio Doglioni, Clelia Di Serio, Luca Biasco, Antonia Follenzi, Luigi Naldini, Claudio Bordignon, Maria Grazia Roncarolo, and Alessandro Aiuti*
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy
Department MISEMB, University of Siena, Siena, Italy
Pathology Unit, Department of Oncology, San Raffaele H Scientific Institute, Milan, Italy
University Statistics Centre for Biomedical Sciences, Universita Vita-Salute San Raffaele, Milan, It
San Raffaele Telethon Institute for Gene Therapy
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET). Universita Vita-Salute, Milan, Italy
* Corresponding author; email: a.aiuti{at}hsr.it.
Adenosine deaminase (ADA)-deficiency is caused by a
purine metabolic dysfunction leading to severe combined
immunodeficiency (SCID) and multiple organ damage. To
investigate the efficacy of ex vivo gene therapy with
self-inactivating lentiviral vectors (LV) in correcting
this complex phenotype, we used an ADA-/- mouse model
characterized by early post-natal lethality. LV-mediated
ADA gene transfer into bone marrow cells combined to low-
dose irradiation rescued mice from lethality and
restored their growth, similarly to transplantation of
wild type bone marrow. Mixed chimerism with multilineage
engraftment of transduced cells was detected long-term
in transplanted animals. ADA activity was normalized in
lymphocytes and partially corrected in RBC, resulting in
full metabolic detoxification and prevention of severe
pulmonary insufficiency. Moreover, gene therapy restored
normal lymphoid differentiation and immune functions,
including antigen-specific antibody production. Similar
degrees of detoxification and immune reconstitution were
obtained in mice treated early after birth or after one
month of enzyme replacement therapy, mimicking two
potential applications for ADA-SCID. Overall, this study
demonstrates the efficacy of LV gene transfer in
correcting both the immunological and metabolic
phenotypes of ADA-SCID and support the future clinical
use of this approach.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. A. Carbonaro, X. Jin, D. Cotoi, T. Mi, X.-J. Yu, D. C. Skelton, F. Dorey, R. E. Kellems, M. R. Blackburn, and D. B. Kohn
Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion
Blood,
June 15, 2008;
111(12):
5745 - 5754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. K. Johansson, T. J. de Vries, T. Schoenmaker, M. Ehinger, A. C. M. Brun, A. Fasth, S. Karlsson, V. Everts, and J. Richter
Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice
Blood,
June 15, 2007;
109(12):
5178 - 5185.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
