Identification of Hematopoietic Stem Cell–Specific miRNAs Enables Gene Therapy of Globoid Cell Leukodystrophy

Gentner, Bernhard; Visigalli, Ilaria; Hiramatsu, Hidefumi; Lechman, Eric R.; Ungari, Silvia; Giustacchini, Alice; Schira, Giulia; Amendola, Mario; Quattrini, Angelo; Martino, Sabata; Orlacchio, Aldo; Dick, John E.; Biffi, Alessandra; Naldini, Luigi

doi:10.1126/scitranslmed.3001522

Cited by 183 publications

(189 citation statements)

References 39 publications

(57 reference statements)

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“…Modifying these cells to allow better enzyme replacement could be a promising approach in treating symptomatic patients. Recently, for instance, enhancing GALC expression by lentiviral gene transduction in hematopoietic stem cells prior to their transplantation into twi mice has been reported, which moderately enhanced the effect of BMT [98].…”

Section: Transplantation Of Cells Into the Twi Mousementioning

confidence: 99%

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

2011

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The leukodystrophies are rare and serious genetic disorders of the central nervous system that primarily affect children who frequently die early in life or have significantly delayed motor and mental milestones that result in long-term disability. Although with some of these disorders, early intervention with bone marrow or cord blood transplantation has been proven useful, it has not yet been determined that such therapies promote myelin repair of the central nervous system. Research on experimental therapies aimed at myelin repair is aided by the ability to test cell replacement strategies in genetic models in which the mutations and neuropathology match the human disorder. Thus, models exist of Pelizaeus-Merzbacher disease and the lysosomal storage disorder, Krabbe disease, which reflect the clinical and pathological course of the human disorders. Collectively, animals with mutations in myelin genes are called the myelin mutants, and they include rodent models such as the shiverer mouse that have been extensively used to study myelination by exogenous cell transplantation. These studies have encompassed many permutations of the age of the recipient, type of transplanted cell, site of engraftment, and so forth, and they offer hope that the scaling up of myelin produced by transplanted cells will have clinical significance in treating patients. Here we review these models and discuss their relative importance and use in such translational approaches. We discuss how grafts are identified and functional outcomes are measured. Finally, we briefly discuss the cells that have been successfully transplanted, which may be used in future clinical trials.

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Section: Transplantation Of Cells Into the Twi Mousementioning

confidence: 99%

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

2011

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“…Lentiviral bidirectional miRNA reporter vectors (Bd.LVs) have been described before [19]. For initial experiments, monocistronic LVs (PGK.GFP, EF1alpha.GFP, EF1alpha.RFP) were used.…”

Section: Lentiviral Plasmidsmentioning

confidence: 99%

A microRNA-Based System for Selecting and Maintaining the Pluripotent State in Human Induced Pluripotent Stem Cells

et al. 2011

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Induced pluripotent stem cell (iPSC) technology has provided researchers with a unique tool to derive disease-specific stem cells for the study and possible treatment of degenerative disorders with autologous cells. The low efficiency and heterogeneous nature of reprogramming is a major impediment to the generation of personalized iPSC lines. Here, we report the generation of a lentiviral system based on a microRNA-regulated transgene that enables for the efficient selection of mouse and human pluripotent cells. This system relies on the differential expression pattern of the mature form of microRNA let7a in pluripotent versus committed or differentiated cells. We generated microRNA responsive green fluorescent protein and Neo reporters for specific labeling and active selection of the pluripotent cells in any culture condition. We used this system to establish Rett syndrome and Parkinson's disease human iPSCs. The presented selection procedure represents a straightforward and powerful tool for facilitating the derivation of patient-specific iPSCs.

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“…Retinal promoters have been used with lentivirus vectors in the eye to achieve selective expression [72]. An elegant approach to restricting transgene expression to certain cells types was demonstrated by Dr. Naldini's group using endogenous microRNA (miRNA) machinery [73]. In this strategy, the goal is to "knock-down" transgene expression (at the mRNA level) in nontarget cells expressing high levels of a particular miRNA by including a binding site for this miRNA in the 3′-untranslated region (UTR) of the transgene message, leaving expression in target cells with low levels of this miRNA.…”

Section: Virus-based Systemsmentioning

confidence: 99%

Gene Therapy for the Nervous System: Challenges and New Strategies

et al. 2014

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Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

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Identification of Hematopoietic Stem Cell–Specific miRNAs Enables Gene Therapy of Globoid Cell Leukodystrophy

Cited by 183 publications

References 39 publications

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

A microRNA-Based System for Selecting and Maintaining the Pluripotent State in Human Induced Pluripotent Stem Cells

Gene Therapy for the Nervous System: Challenges and New Strategies

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