Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

@article{Aiuti2013LentiviralHS,
  title={Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome},
  author={Alessandro Aiuti and Luca Biasco and Samantha Scaramuzza and Francesca Ferrua and Maria Pia Cicalese and Cristina Baricordi and Francesca Dionisio and Andrea Calabria and Stefania Giannelli and Maria Carmina Castiello and Marita Bosticardo and Costanza Evangelio and Andrea Angelo Assanelli and Miriam Casiraghi and Sara di Nunzio and Luciano Callegaro and Claudia Benati and P Rizzardi and Danilo Pellin and Clelia Di Serio and Manfred Schmidt and Christof von Kalle and Jason Gardner and Nalini A. L. Mehta and Victor Neduva and David J. Dow and Anne Galy and Roberto Miniero and Andrea Finocchi and Ayşe Metin and Pinaki Prosad Banerjee and Jordan S. Orange and Stefania Galimberti and Maria Grazia Valsecchi and Alessandra Biffi and Eugenio Montini and Anna Villa and Fabio Ciceri and Maria Grazia Roncarolo and Luigi Naldini},
  journal={Science},
  year={2013},
  volume={341}
}
Introduction Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency characterized by eczema, thrombocytopenia, infections, and a high risk of developing autoimmunity and cancer. In a recent clinical trial, a γ-retroviral vector was used to introduce a functional WAS gene into autologous hematopoietic stem/progenitor cells (HSCs), followed by reinfusion of the gene-corrected HSCs into the patients. This strategy provided clinical benefit but resulted in expansion and malignant… 

Gene Therapy for Wiskott-Aldrich Syndrome—Long-Term Efficacy and Genotoxicity

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It is suggested that with improved vector design, gene therapy may be feasible and effective for patient with Wiskott-Aldrich syndrome, and the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.

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Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome

TLDR
A CRISPR/Cas9-based genome editing strategy is developed that allows the precise correction of Wiskott-Aldrich Syndrome in vitro and in vivo with high efficiency and no major genotoxicity was associated with the gene editing process.

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TLDR
After trials and errors, inactivating lentiviral vectors carrying the WAS gene were successfully evaluated in clinical trials, demonstrating cure of the disease except for insufficient resolution of the platelet defect.

Cellular Therapies for Wiskott-Aldrich Syndrome

TLDR
Hematopoietic stem cell gene therapy has been developed as an alternative, but oncogene activation secondary to insertional mutagenesis can lead to oncogenesis, and more recent therapeutic approaches include the use of self-inactivating lentiviral vectors, promising a better safety-to-risk ratio.

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TLDR
Risks and benefits of GT and allogeneic hematopoietic stem cell transplantation must be weighted considering remission, safety profiles, side effects, availability and cost effectiveness, despite long-term clinical benefits, uncontrolled clonal expansion remains a critical limitation.

Clinical applications of gene therapy for primary immunodeficiencies.

TLDR
The recent results of LV-mediated gene therapy for WAS showing stable multilineage engraftment leading to hematological and immunological improvement are presented and the differences with respect to the WAS RV trial are discussed.

A possible turning point in the hematopoietic stem cell gene therapy for primary immunodeficiency diseases? Lentiviral vectors could take the place of retroviral vectors

  • T. Ariga
  • Medicine, Biology
    Expert review of clinical immunology
  • 2013
TLDR
A detailed study of the vector integration sites was undertaken and concluded that lentiviral HSC gene therapy was safer than retroviral gene therapy.

Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

TLDR
The reconstitution of ARSA activity in the cerebrospinal fluid and the arrested progression of neurodegenerative disease in the three treated patients demonstrate that the transplanted cells, or their progeny, can seed the nervous system and deliver therapeutic levels of active enzyme.
...

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