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

Cartier, Nathalie; Hacein‐Bey‐Abina, Salima; Bartholomae, Cynthia C.; Veres, Gábor; Schmidt, Manfred; Kutschera, Ina; Vidaud, Michel; Abel, Ulrich; Dal-Cortivo, Liliane; Caccavelli, Laure; Mahlaoui, Nizar; Kiermer, Véronique; Mittelstaedt, Denice; Bellesme, Céline; Lahlou, Najiba; Lefrère, François; Blanche, Stéphane; Audit, Muriel; Payen, Emmanuel; Leboulch, Philippe; L’homme, Bruno; Bougnères, Pierre; Kalle, Christof von; Fischer, Alain; Cavazzana, Marina; Aubourg, Patrick

doi:10.1126/science.1171242

Cited by 1,369 publications

(1,049 citation statements)

References 25 publications

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“…Encouraging results were obtained in a clinical trial using lentiviral vectors, with integration in specific genomic regions not associated with oncogenic selection. 44,45 The availability of Brtl mice will allow us to test such an approach for siRNA delivery by transducing Brtl mesenchymal stem cells with the lentiviral vector expressing the effective F-shRNA and transplanting them back to Brtl, as previously described. 20 Other novel tools may allow us to more safely manipulate mammalian cells than the use of lentivirus vectors.…”

Section: Discussionmentioning

confidence: 99%

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

et al. 2013

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Gene silencing approaches have the potential to become a powerful curative tool for a variety of monogenic diseases caused by gain-of-function mutations. Classical osteogenesis imperfecta (OI), a dominantly inherited bone dysplasia, is characterized in its more severe forms by synthesis of structurally abnormal type I collagen, which exerts a negative effect on extracellular matrix. Specific suppression of the mutant (Mut) allele would convert severe OI forms to the mild type caused by a quantitative defect in normal collagen. Here, we describe the in vitro and ex vivo investigation of a small interfering RNA (siRNA) approach to allele-specific gene silencing using Mut Col1a1 from the Brtl mouse, a well-characterized model for classical human OI. A human embryonic kidney cell line, which expresses the firefly luciferase gene, combined with either wild-type or Mut Brtl Col1a1 exon 23 sequences, was used for the first screening. The siRNAs selected based on their specificity and the corresponding short hairpin RNAs (shRNAs) subcloned in a lentiviral vector were evaluated ex vivo in Brtl fibroblasts for their effect on collagen transcripts and protein. A preferential reduction of the Mut allele of up to 52% was associated with about 40% decrease of the Mut protein, with no alteration of cell proliferation. Interestingly, a downregulation of HSP47, a specific collagen chaperone known to be upregulated in some OI cases, was detected. Our data support further testing of shRNAs and their delivery by lentivirus as a strategy to specifically suppress the Mut allele in mesenchymal stem cells of OI patients for autologous transplantation.

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Section: Discussionmentioning

confidence: 99%

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

et al. 2013

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“…Very recently, HSC gene therapy using a lentiviral vector has been reported to be successful in arresting the progression of CCALD in two patients at an early stage, 11 however, the mechanisms of the therapeutic effect in this therapy still remain obscure, which may be because of replacement of the ABCD1 gene, that of normal stem cells or other factors. Further studies concerning the modulation of VLCFA or the prevention of cerebral involvement should be accelerated for suffering patients and their families, as well as the identification of predictive factors for the onset of brain involvement as the keys to solving the problems.…”

Section: Early Intervention and Long-term Follow-up System For Presymmentioning

confidence: 99%

X-linked adrenoleukodystrophy: Diagnostic and follow-up system in Japan

et al. 2010

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X-linked adrenoleukodystrophy (ALD) is an intractable neurodegenerative disease associated with the accumulation of very longchain saturated fatty acids (VLCFA) in tissues and body fluids. We have established a Japanese referral center for the diagnosis of ALD, using VLCFA measurements and mutation analysis of the ABCD1 gene, and have identified 60 kinds of mutations in 69 Japanese ALD families, which included 38 missense mutations, 6 nonsense mutations, 8 frame-shift mutations, 3 amino acid deletions, 2 exon-skip mutations and 3 large deletions. A total of 24 kinds of mutations (40%) were identified only in Japanese patients by referring to the current worldwide ALD mutation database. There was no clear correlation between these mutations and phenotypes of 81 male patients in these 69 families. About 12% of the individuals with ALD had de novo mutations by mutation analysis in the male probands and their mothers, which should be helpful data for genetic counseling. The only effective therapy for the cerebral form of ALD should be hematopoietic stem cell transplantation at the early stages of the cerebral symptoms, therefore, we performed presymptomatic diagnosis of ALD by extended familial screening of the probands with careful genetic counseling, and established a long follow-up system for these patients to prevent the progression of brain involvement and to monitor the adrenocortical insufficiency. Further elucidation of pathology in ALD, especially concerning the mechanisms of the onset of brain involvement, is expected.

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“…[28] Another successful use of lentiviral vector in a clinical trial was reported for the treatment of X-linked adrenoleukodystrophy due to a deficiency of the ABCD1 gene. [29] In this trial, progressive cerebral demyelination in two patients was successfully blocked for 14-16 months after lentiviral delivery of wild-type ABCD1 to CD34+ cells ex vivo. [29] These results encourage more clinical investigation into the use of lentiviral vectors for human gene therapy.…”

Section: Lentiviralmentioning

confidence: 95%

“…[29] In this trial, progressive cerebral demyelination in two patients was successfully blocked for 14-16 months after lentiviral delivery of wild-type ABCD1 to CD34+ cells ex vivo. [29] These results encourage more clinical investigation into the use of lentiviral vectors for human gene therapy.…”

Section: Lentiviralmentioning

confidence: 95%

Advances in Gene Delivery Systems

et al. 2011

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The transfer of genes into cells, both in vitro and in vivo, is critical for studying gene function and conducting gene therapy. Methods that utilize viral and nonviral vectors, as well as physical approaches, have been explored. Viral vector-mediated gene transfer employs replication-deficient viruses such as retro-virus, adenovirus, adeno-associated virus and herpes simplex virus. A major advantage of viral vectors is their high gene delivery efficiency. The nonviral vectors developed so far include cationic liposomes, cationic polymers, synthetic peptides and naturally occurring compounds. These nonviral vectors appear to be highly effective in gene delivery to cultured cells in vitro but are significantly less effective in vivo. Physical methods utilize mechanical pressure, electric shock or hydrodynamic force to transiently permeate the cell membrane to transfer DNA into target cells. They are simpler than viral-and nonviral-based systems and highly effective for localized gene delivery. The past decade has seen significant efforts to establish the most desirable method for safe, effective and target-specific gene delivery, and good progress has been made. The objectives of this review are to (i) explain the rationale for the design of viral, nonviral and physical methods for gene delivery; (ii) provide a summary on recent advances in gene transfer technology; (iii) discuss advantages and disadvantages of each of the most commonly used gene delivery methods; and (iv) provide future perspectives.

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

Cited by 1,369 publications

References 25 publications

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

X-linked adrenoleukodystrophy: Diagnostic and follow-up system in Japan

Advances in Gene Delivery Systems

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