Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in X‐Linked Adrenoleukodystrophy

Cartier, Nathalie; Aubourg, Patrick

doi:10.1111/j.1750-3639.2010.00394.x

Cited by 124 publications

(105 citation statements)

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“…Therapeutic options remain scarce, with a small window of opportunity to apply allogeneic bone marrow transplant or new gene therapy for CCALD. 14 No therapeutic options are currently available for AMN. 15 The classical inactivation of Abcd1 in mice (Abcd1 -) results in the accumulation of VLCFA in target organs such as the central nervous system and adrenals.…”

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confidence: 99%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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confidence: 99%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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“…Successful clinical trials have been performed in patients suffering from adrenoleukodystrophy, Parkinson's disease, chronic lymphocytic leukemia, acute lymphocytic leukemia, multiple myeloma, and hemophilia (26,27). Initially, the prevailing gene therapy methods involved recombinant viruses, but nonviral methods (transfection molecules) have become increasingly successful.…”

Section: Genetic Therapymentioning

confidence: 99%

Cloning humans? Biological, ethical, and social considerations

Ayala

2015

Proc. Natl. Acad. Sci. U.S.A.

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There are, in mankind, two kinds of heredity: biological and cultural. Cultural inheritance makes possible for humans what no other organism can accomplish: the cumulative transmission of experience from generation to generation. In turn, cultural inheritance leads to cultural evolution, the prevailing mode of human adaptation. For the last few millennia, humans have been adapting the environments to their genes more often than their genes to the environments. Nevertheless, natural selection persists in modern humans, both as differential mortality and as differential fertility, although its intensity may decrease in the future. More than 2,000 human diseases and abnormalities have a genetic causation. Health care and the increasing feasibility of genetic therapy will, although slowly, augment the future incidence of hereditary ailments. Germ-line gene therapy could halt this increase, but at present, it is not technically feasible. The proposal to enhance the human genetic endowment by genetic cloning of eminent individuals is not warranted. Genomes can be cloned; individuals cannot. In the future, therapeutic cloning will bring enhanced possibilities for organ transplantation, nerve cells and tissue healing, and other health benefits.

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“…Clinical successes the last 5 years have breathed new air in the field of gene therapy like i.e. the treatment of X-linked SCID, ADA-SCID (Cartier and Aubourg, 2010;Aiuti et al, 2002), Xadrenoleukodystrophy (Cartier et al, 2009) and Wiskott-Aldrich Syndrome (WAS) (Boztug et al, 2010;Aiuti et al, 2013) metachromatic leukodystrophy by using ex vivo gene transfer into bone marrow hematopoietic stem cells and autologous transplantation or by direct gene transfer in vivo as in the cases of Leber congenital amaurosis (Bainbridge et al, 2008;Simonelli et al, 2010) and Parkinson's disease (LeWitt et al, 2011;Palfi et al, 2013) ONCOLYTIC VIRUSES AND VECTOR SYSTEMS FOR GENE DELIVERY There are several virus families and representatives of each family that are currently engaged in the battle with cancer. Oncolytic viruses have a native capacity of cell lysis and so innate ability of killing.…”

Section: Gene Delivery -Viral and Non-viral Sytemsmentioning

confidence: 99%

Anticancer Gene Transfer for Cancer Gene Therapy

Pazarentzos

Mazarakis

2014

Advances in Experimental Medicine and Biology

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Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by nonspecific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field.

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Hematopoietic Stem Cell Transplantation and Hematopoietic Stem Cell Gene Therapy in X‐Linked Adrenoleukodystrophy

Cited by 124 publications

References 51 publications

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Cloning humans? Biological, ethical, and social considerations

Anticancer Gene Transfer for Cancer Gene Therapy

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