Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

  title={Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy},
  author={Alessandra Biffi and Eugenio Montini and Laura Lorioli and Martina Cesani and Francesca Fumagalli and Tiziana Plati and Cristina Baldoli and Sabata Martino and Andrea Calabria and Sabrina Canale and Fabrizio Benedicenti and Giuliana Vallanti and Luca Biasco and Simone Leo and Nabil Kabbara and Gianluigi Zanetti and William B. Rizzo and Nalini A. L. Mehta and Maria Pia Cicalese and Miriam Casiraghi and Jaap Jan Boelens and Ubaldo Del Carro and David J. Dow and Manfred Schmidt and Andrea Angelo Assanelli and Victor Neduva and Clelia Di Serio and Elia Stupka and Jason Gardner and Christof von Kalle and Claudio Bordignon and Fabio Ciceri and Attilio Rovelli and Maria Grazia Roncarolo and Alessandro Aiuti and Maria Sessa and Luigi Naldini},
Introduction Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. The disease primarily affects children and invariably leads to premature death. In previous work with a mouse model of MLD, we used a lentiviral vector (LV) to introduce a functional ARSA gene into hematopoietic stem cells (HSCs) ex vivo and showed that reinfusion of the engineered HSCs prevented and corrected disease manifestations in the animals. To… 

Hematopoietic stem cell transplantation for metachromatic leukodystrophy

HSC-based approaches would require the evaluation of long-term follow-up on neurological and transplant-related outcomes of larger cohorts of patients, in order to rationally define indication to treatment for MLD patients.

Gene therapy for metachromatic leukodystrophy

Preclinical data from the group and from others that support the use of a gene therapy with AAVrh.10 serotype for clinical development as a treatment for MLD are summarized and the potential of gene therapy for LDs especially for Krabbe disease is highlighted.

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

A clinical protocol based on lentiviral vector (LV) gene transfer into autologous hematopoietic stem/progenitor cells (HSCs) resulted in robust, stable, and long-term engraftment of gene-corrected HSCs in the patients’ bone marrow, and the findings support the use of LV gene therapy to treat patients with WAS.

Gene Therapy for Nonmalignant Hematology

  • Xiuyan WangI. Rivière
  • Biology, Medicine
    Advances and Controversies in Hematopoietic Transplantation and Cell Therapy
  • 2018
The discovery and maturation of gene-editing platforms, including zinc-finger nuclease (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, offer exciting prospective strategies for further improving gene therapy by targeting the repair of diseased genes.

Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I

An overview of the most recent scientific advances in HSC-based gene therapy approaches for the treatment of LSDs with particular focus on metachromatic leukodystrophy (MLD) and mucopolysaccharidosis type I (MPS-I).

Hematopoietic Stem‐Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Early results of this study suggest that Lenti‐D gene therapy may be a safe and effective alternative to allogeneic stem‐cell transplantation in boys with early‐stage cerebral adrenoleukodystrophy.

Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice

The results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.

A shot in the bone corrects a genetic disease.

  • B. Brown
  • Biology
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2015
A clever approach for hemophilia HSPC-GT is described that direct injection of LVs into the bone marrow of mice can stably transfer a FVIII transgene into HSPCs and their progeny without the need for BMT.

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model

Findings provide first evidence of the efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application.



Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy

Lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD, and progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT.

Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice.

Results indicate that the recruitment of gene-modified, enzyme-overexpressing microglia makes the enzyme bioavailable to the brain and makes therapeutic efficacy and disease correction attainable.

Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells.

Ex vivo gene therapy had a significantly higher therapeutic impact than WT HSC transplantation, indicating a critical role for enzyme overexpression in the HSC progeny and indicates that transplantation of LV-transduced autologous HSCs represents a potentially efficacious therapeutic strategy for MLD and possibly other neurodegenerative disorders.

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

A clinical protocol based on lentiviral vector (LV) gene transfer into autologous hematopoietic stem/progenitor cells (HSCs) resulted in robust, stable, and long-term engraftment of gene-corrected HSCs in the patients’ bone marrow, and the findings support the use of LV gene therapy to treat patients with WAS.

Gene therapy for leukodystrophies.

A gene therapy strategy aiming at transferring the disease gene into autologous hematopoietic stem cells (HSCs) using lentiviral vectors has been developed and has already entered into the clinics for X-ALD and MLD.

Safety of arylsulfatase A overexpression for gene therapy of metachromatic leukodystrophy.

Data indicate that from the perspective of clinical translation, therapeutic levels of ARSA overexpression can be safely achieved and demonstrate an experimental platform for the preclinical assessment of the safety of new gene therapy approaches.

Metachromatic leukodystrophy: an overview of current and prospective treatments

Autologous hematopoietic stem/progenitor cells can be genetically modified to constitutively express supra-physiological levels of arylsulfatase-A and may become a quantitatively more effective source of functional enzyme than normal donor cells when transplanted in patients with MLD, thus possibly overcoming the limits of HSCT.

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model.

It is demonstrated here that HSC gene therapy, based on lentiviral vectors, completely corrects disease manifestations in the mouse model and provides evidence of an efficacious treatment for MPS I Hurler patients, warranting future development toward clinical testing.

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

It is shown that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI 1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.

Stem-cell gene therapy for the Wiskott-Aldrich syndrome.

Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis in the Wiskott-Aldrich syndrome.