32 Side effects in gene therapy with hematopoietic cells

Baum, CM; Li, Z.; Modlich, Ute; Meyer, Johann; Schiedlmeier, Bernhard; Klump, Hannes; Beutel, Gernot; Kalle, Christoph von; Kraunus, Janine; Bohne, Jens

doi:10.1016/s0378-4274(03)90031-2

Cited by 2 publications

(2 citation statements)

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“…Insertional oncogenesis has been observed in 5 of these 22 patients, all occurring in patients with X-linked SCID [135]. The potential risk of transformation in thalassemic patients treated with an erythroid-specific lentiviral vector such as TNS9 should be less by virtue of the restricted expression of the globin vector [136][137][138], the innocuous properties of the ß chain of hemoglobin, and the more favorable integration site distribution of lentiviral vectors compared to gamma-retroviral vectors [63,139,140].…”

Section: Risks Of Globin Gene Therapymentioning

confidence: 99%

Stem Cell Engineering for the Treatment of Severe Hemoglobinopathies

Sadelain

Boulad²,

Lisowki³

et al. 2008

CMM

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The beta-thalassemias and sickle cell anemia are severe congenital anemias for which there is presently no curative therapy other than allogeneic bone marrow transplantation. This therapeutic option, however, is not available to most patients due to the lack of an HLA-matched bone marrow donor. Emerging modalities based on cell engineering offer new prospects for potentially curative approaches that are applicable to more patients. The first is based on the transfer of a regulated globin gene in autologous hematopoietic stem cells (HSCs). This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid-specific, differentiation and stage-restricted, elevated, position-independent, and sustained over time. Following the original report by May et al., several groups have reported that lentiviral vectors encoding slightly different combinations of proximal and distal transcriptional control elements of the normal human beta-globin gene permit lineage-specific and elevated beta-globin expression in vivo, resulting in therapeutic hemoglobin production and correction of anemia in beta-thalassemic mice. Clinical studies utilizing the TNS.3 vector are likely to be initiated in the US in 2009. While the addition of the wild-type beta-globin gene is naturally suited for treating beta-thalassemia, several alternatives have been proposed for the treatment of sickle cell disease, using either gamma- or mutant beta-globin gene addition, trans-splicing or RNA interference. The recent discovery that adult somatic cells can be reprogrammed to become pluripotent stem cells from which HSCs can be derived, provides yet another venue for developing stem cell engineering using either lentiviral vectors or homologous recombination techniques. Altogether, these recent advances bode well for the advent of curative stem cell-based therapies.

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Section: Risks Of Globin Gene Therapymentioning

confidence: 99%

Stem Cell Engineering for the Treatment of Severe Hemoglobinopathies

Sadelain

Boulad²,

Lisowki³

et al. 2008

CMM

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“…The observed complications in three of these four children stem from vector-mediated insertional mutagenesis events near the LIM Domain Only 2 ( LMO2 ) oncogene [23, 24]. These tragic results highlight the need for continued development of improved gene transfer technologies that avoid undesired side effects and ensure the safety of the patient [25, 26]. …”

Section: Introductionmentioning

confidence: 99%

Site-specific integration of retroviral DNA in human cells using fusion proteins consisting of human immunodeficiency virus type 1 integrase and the designed polydactyl zinc-finger protein E2C

Wang

Jian

et al. 2009

Methods

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During the life cycle of retroviruses, establishment of a productive infection requires stable joining of a DNA copy of the viral RNA genome into host cell chromosomes. Retroviruses are thus promising vectors for the efficient and stable delivery of genes in therapeutic protocols. Integration of retroviral DNA is catalyzed by the viral enzyme integrase (IN), and one salient feature of retroviral DNA integration is its lack of specificity, as many chromosomal sites can serve as targets for integration. Despite the promise for success in the clinic, one major drawback of the retrovirus-based vector is that any unintended insertion events from the therapy can potentially lead to deleterious effects in patients, as demonstrated by the development of malignancies in both animal and human studies. One approach to directing integration into predetermined DNA sites is fusing IN to a sequencespecific DNA-binding protein, which results in a bias of integration near the recognition site of the fusion partner. Encouraging results have been generated in vitro and in vivo using fusion protein constructs of human immunodeficiency virus type 1 IN and E2C, a designed polydactyl zinc-finger protein that specifically recognizes an 18-base pair DNA sequence. This review focuses on the method for preparing infectious virions containing the IN fusion proteins and on the quantitative PCR assays for determining integration site specificity. Efforts to engineer IN to recognize specific target DNA sequences within the genome may lead to development of effective retroviral vectors that can safely deliver gene-based therapeutics in a clinical setting.

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32 Side effects in gene therapy with hematopoietic cells

Cited by 2 publications

References 0 publications

Stem Cell Engineering for the Treatment of Severe Hemoglobinopathies

Stem Cell Engineering for the Treatment of Severe Hemoglobinopathies

Site-specific integration of retroviral DNA in human cells using fusion proteins consisting of human immunodeficiency virus type 1 integrase and the designed polydactyl zinc-finger protein E2C

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