GENE THERAPY: Twenty-First Century Medicine

Verma, Inder M.; Weitzman, Matthew D.

doi:10.1146/annurev.biochem.74.050304.091637

Cited by 542 publications

(399 citation statements)

References 169 publications

(152 reference statements)

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“…This property is the basis of an increasing range of applications of HSC transplants to treat various malignant and genetic disorders [1,2]. Further improvements in the safety and therapeutic utility of HSC transplants can be readily envisaged if robust methods for largescale ex vivo expansion of HSCs were available.…”

Section: Introductionmentioning

confidence: 99%

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

Ohta

Sekulovic

Bakovic

et al. 2007

Experimental Hematology

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Objective-Strategies to expand hematopoietic stem cells (HSCs) ex vivo are of key interest. The objective of this study was to resolve if ability of HOXB4, previously documented to induce a significant expansion of HSCs in culture, may extend to other HOX genes and also to further analyze the HOX sequence requirements to achieve this effect.Methods-To investigate the ability of Nucleoporin98-Homeobox fusion genes to stimulate HSC self-renewal, we evaluated their presence in 10-to 20-day cultures of transduced mouse bone marrow cells. Stem cell recovery was measured by limiting-dilution assay for long-term competitive repopulating cells (CRU Assay).Results-These experiments revealed remarkable expansions of Nucleoporin98-Homeoboxtransduced HSCs (1000-fold to 10,000-fold over input) in contrast to the expected decline of HSCs in control cultures. Nevertheless, the Nucleoporin98-Homeobox-expanded HSCs displayed no proliferative senescence and retained normal lympho-myeloid differentiation activity and a controlled pool size in vivo. Analysis of proviral integration patterns showed the cells regenerated in vivo were highly polyclonal, indicating they had derived from a large proportion of the initially targeted HSCs. Importantly, these effects were preserved when all HOX sequences flanking the homeodomain were removed, thus defining the homeodomain as a key and independent element in the fusion.Conclusion-These findings create new possibilities for investigating HSCs biochemically and genetically and for achieving clinically significant expansion of human HSCs.The self-renewal function of hematopoietic stem cells (HSCs) is essential to their ability to sustain lifelong hematopoiesis and to regenerate the hematopoietic system after myeloablative treatments. This property is the basis of an increasing range of applications of HSC transplants to treat various malignant and genetic disorders [1,2]. Further improvements in the safety and therapeutic utility of HSC transplants can be readily envisaged if robust methods for largescale ex vivo expansion of HSCs were available. For example, the low absolute numbers of HSCs in most cord blood samples [3] [4] restrict the clinical utility of these products. A method for significantly expanding HSCs could not only address these insufficiencies but also broaden the exploitation of reduced conditioning regimens and associated therapeutic benefits.One approach that has allowed some HSC expansion in vitro to be achieved has focused on the identification of optimized combinations and concentrations of externally acting growth factors and related molecules [5][6][7][8][9][10][11][12]. A complementary approach has been to identify intrinsic regulators such as transcription factors [13] and key mediators of signaling pathways [14,15] that can be manipulated to activate or promote HSC self-renewal divisions. A striking example of the latter strategy is the use of retrovirally engineered overexpression of the homeobox transcription factor HOXB4 to stimulate expansions of HSC numb...

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Section: Introductionmentioning

confidence: 99%

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

Ohta

Sekulovic

Bakovic

et al. 2007

Experimental Hematology

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“…In contrast to more commonly studied oncoretroviruses, they can infect both mitotic and post-mitotic cells (Naldini and Verma, 2000;Verma and Weitzman, 2005). Human Immunodeficiency Virus type I (HIV) is classified as a lentivirus.…”

Section: Lentivirus (Lv)mentioning

confidence: 99%

“…The LTRs are important for integration, transcription and polyadenylation. Lentiviruses are more complex than other retroviruses since they contain other regulatory genes such as tat and rev, as well as other accessory genes including vif, vpr, vpu, and nef (Naldini et al, 1996a;Naldini and Verma, 2000;Verma and Weitzman, 2005).…”

Section: Lentivirus (Lv)mentioning

confidence: 99%

“…Viruses have evolved over millions of years to efficiently transfer genes that allow them to survive and replicate in mammalian hosts (Verma and Weitzman, 2005). Characterization of the life cycle of wild-type viruses has allowed the engineering of recombinant viral vectors that are deficient in replication functions but are capable of infecting the cell to introduce foreign genes.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, production of clinical grade vectors becomes an important issue for investigators planning to use these reagents in a clinical trial. Other viruses have been engineered into viral vectors and are in various stages of development but are beyond the scope of this review (Verma and Weitzman, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Viral vectors for in vivo gene transfer in Parkinson's disease: Properties and clinical grade production

Mandel

Bürger

Snyder

2008

Experimental Neurology

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Because Parkinson's disease is a progressive degenerative disorder that is mainly confined to the basal ganglia, gene transfer to deliver therapeutic molecules is an attractive treatment avenue. The present review focuses on direct in vivo gene transfer vectors that have been developed to a degree that they have been successfully used in animal model of Parkinson's disease. Accordingly, the properties of recombinant adenovirus, recombinant adeno-associated virus, herpes simplex virus, and lentivirus are described and contrasted. In order for viral vectors to be developed into clinical grade reagents, they must be manufactured and tested to precise regulatory standards. Indeed, clinical lots of viral vectors can be produced in compliance with current Good Manufacturing Practices (cGMPs) regulations using industry accepted manufacturing methodologies, manufacturing controls, and quality systems. The viral vector properties themselves combined with physiological product formulations facilitate long-term storage and direct in vivo administration.

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Gene Therapy

Ginn

Alexander

2005

Encyclopedia of Statistical Sciences

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Conducting a clinical trial poses a unique set of challenges that must be addressed to ensure the safety of human subjects. In this article, we discuss issues that relate in particular to gene therapy clinical trials. These issues include the choice of gene delivery system, the need for extensive preclinical testing to ensure the feasibility and safety of the approach, and careful monitoring of subjects for short‐ and long‐term toxicity associated with the gene transfer protocol.

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GENE THERAPY: Twenty-First Century Medicine

Cited by 542 publications

References 169 publications

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

Viral vectors for in vivo gene transfer in Parkinson's disease: Properties and clinical grade production

Gene Therapy

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