Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

@article{Biffi2013LentiviralHS,
  title={Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy},
  author={A. Biffi and E. Montini and L. Lorioli and M. Cesani and F. Fumagalli and T. Plati and C. Baldoli and S. Martino and A. Calabria and S. Canale and F. Benedicenti and G. Vallanti and L. Biasco and Simone Leo and N. Kabbara and G. Zanetti and W. Rizzo and N. Mehta and M. Cicalese and Miriam Casiraghi and J. Boelens and U. Del Carro and D. Dow and Manfred Schmidt and A. Assanelli and Victor Neduva and C. Di Serio and E. Stupka and J. Gardner and C. von Kalle and C. Bordignon and F. Ciceri and A. Rovelli and M. Roncarolo and A. Aiuti and M. Sessa and L. Naldini},
  journal={Science},
  year={2013},
  volume={341}
}
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… Expand
Hematopoietic stem cell transplantation for metachromatic leukodystrophy
TLDR
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. Expand
Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome
TLDR
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. Expand
Gene therapy for metachromatic leukodystrophy
TLDR
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. Expand
Gene Therapy for Nonmalignant Hematology
TLDR
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. Expand
Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I
TLDR
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). Expand
Hematopoietic Stem‐Cell Gene Therapy for Cerebral Adrenoleukodystrophy
TLDR
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. Expand
Preclinical Efficacy and Safety Evaluation of Hematopoietic Stem Cell Gene Therapy in a Mouse Model of MNGIE
TLDR
This report confirms and supplements previous work on the efficacy of HSCGT in reducing the toxic metabolites in Tymp−/−Upp1+/− mice, using a clinically applicable gene transfer vector and a highly efficient gene transfer method, and importantly demonstrates phenotypic correction with a favorable risk profile, warranting further development toward clinical implementation. Expand
Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice
TLDR
The results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD. Expand
A shot in the bone corrects a genetic disease.
  • B. Brown
  • Medicine
  • Molecular therapy : the journal of the American Society of Gene Therapy
  • 2015
TLDR
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. Expand
Therapeutic benefit of lentiviral-mediated neonatal intracerebral gene therapy in a mouse model of globoid cell leukodystrophy
TLDR
This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 73 REFERENCES
Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
TLDR
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. Expand
Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice.
TLDR
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. Expand
Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells.
TLDR
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. Expand
Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome
TLDR
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. Expand
Gene therapy for leukodystrophies.
TLDR
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. Expand
Safety of arylsulfatase A overexpression for gene therapy of metachromatic leukodystrophy.
TLDR
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. Expand
Metachromatic leukodystrophy: an overview of current and prospective treatments
TLDR
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. Expand
Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model.
TLDR
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. Expand
Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease
TLDR
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. Expand
Stem-cell gene therapy for the Wiskott-Aldrich syndrome.
TLDR
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. Expand
...
1
2
3
4
5
...