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Bouchier-Hayes L.,Center for Cell and Gene Therapy | Bouchier-Hayes L.,Baylor College of Medicine | Green D.R.,St Jude Childrens Research Hospital
Cell Death and Differentiation

Despite an abundance of literature on the role of caspase-2 in apoptosis, there exists much controversy about this protease making it difficult to place caspase-2 correctly in the apoptotic cascade, and hence its role in apoptosis remains unclear. The identification of the PIDDosome as a signaling platform for caspase-2 activation prompted intense investigation into the true role of this orphan caspase. What has emerged is the idea that caspase-2 may not be mandatory for apoptosis and that activation of this caspase in response to some forms of stress has other effects on the cell such as regulation of cell cycle progression. This idea is particularly relevent to the discovery that caspase-2 may act as a tumor suppressor. Here, we discuss the proposed mechanisms through which caspase-2 signals, in particular those involving PIDD, and their impact on cellular fate. © 2012 Macmillan Publishers Limited All rights reserved. Source

Rogers G.L.,University of Florida | Suzuki M.,Center for Cell and Gene Therapy | Zolotukhin I.,University of Florida | Markusic D.M.,University of Florida | And 5 more authors.
Journal of Innate Immunity

The immune system represents a significant barrier to successful gene therapy with adeno-associated viral (AAV) vectors. In particular, adaptive immune responses to the viral capsid or the transgene product are of concern. The sensing of AAV by toll-like receptors (TLRs) TLR2 and TLR9 has been suggested to play a role in innate immunity to the virus and may also shape subsequent adaptive immune responses. Here, we investigated the functions of TLR2, TLR9 and the downstream signaling adaptor MyD88 in antibody and CD8+ T-cell responses. Antibody formation against the transgene product occurred largely independently of TLR signaling following gene transfer with AAV1 or AAV2 vectors, whereas loss of signaling through the TLR9-MyD88 pathway substantially reduced CD8+ T-cell responses. In contrast, MyD88 (but neither of the TLRs) regulated antibody responses to capsid. B cell-intrinsic MyD88 was required for the formation of anti-capsid IgG2c independently of vector serotype or route of administration. However, MyD88-/- mice instead produced anti-capsid IgG1 that emerged with delayed kinetics but nonetheless completely prevented in vivo readministration. We conclude that there are distinct roles for TLR9 and MyD88 in promoting adaptive immune responses to AAV-mediated gene transfer and that there are redundant MyD88-dependent and MyD88-independent mechanisms that stimulate neutralizing antibody formation against AAV. © 2015 S. Karger AG, Basel. Source

Barese C.N.,U.S. National Institutes of Health | Felizardo T.C.,U.S. National Cancer Institute | Sellers S.E.,U.S. National Institutes of Health | Keyvanfar K.,U.S. National Institutes of Health | And 6 more authors.
Stem Cells

The high risk of insertional oncogenesis reported in clinical trials using integrating retroviral vectors to genetically modify hematopoietic stem and progenitor cells (HSPCs) requires the development of safety strategies to minimize risks associated with novel cell and gene therapies. The ability to ablate genetically modified cells in vivo is desirable, should an abnormal clone emerge. Inclusion of "suicide genes" in vectors to facilitate targeted ablation of vector-containing abnormal clones in vivo is one potential safety approach. We tested whether the inclusion of the "inducible Caspase-9" (iCasp9) suicide gene in a gamma-retroviral vector facilitated efficient elimination of vector-containing HSPCs and their hematopoietic progeny in vivo long-term, in an autologous non-human primate transplantation model. Following stable engraftment of iCasp9 expressing hematopoietic cells in rhesus macaques, administration of AP1903, a chemical inducer of dimerization able to activate iCasp9, specifically eliminated vector-containing cells in all hematopoietic lineages long-term, suggesting activity at the HSPC level. Between 75% and 94% of vector-containing cells were eliminated by well-tolerated AP1903 dosing, but lack of complete ablation was linked to lower iCasp9 expression in residual cells. Further investigation of resistance mechanisms demonstrated upregulation of Bcl-2 in hematopoietic cell lines transduced with the vector and resistant to AP1903 ablation. These results demonstrate both the potential and the limitations of safety approaches using iCasp9 to HSPC-targeted gene therapy settings, in a model with great relevance to clinical development. Stem Cells 2015;33:91-100 © 2014 AlphaMed Press. Source

Lam S.,Center for Cell and Gene Therapy | Lam S.,Texas Childrens Cancer and Hematology Centers | Lam S.,Baylor College of Medicine | Bollard C.,Center for Cell and Gene Therapy | And 2 more authors.

Antiretroviral therapy has improved the quality of life for HIV+ individuals but efficacy requires strict adherence and treatment is not curative. Recently, the use of T cells as therapeutic agents has been in the spotlight in the settings of post-transplant opportunistic infections and cancer. Whether T-cell therapy can be harnessed for treating HIV remains to be determined but there are a few studies that seek to answer that question. Infusion of ex vivo-expanded HIV-specific T cells showed limited efficacy but no adverse events. Genetically modified T cells expressing CD4 chimeric antigen receptors have recently been shown to have persistence that outperforms chimeric antigen receptors used for cancers. Although the results have not yet been published for many clinical studies using T cells for HIV, preclinical studies and the clinical data that are available highlight the potential for T-cell therapy to decrease or eliminate HIV patients' dependency on antiretroviral therapy. © 2013 Future Medicine Ltd. Source

Brenner M.K.,Center for Cell and Gene Therapy
Cancer Gene Therapy

Cellular therapies for cancer are showing increasing efficacy but their introduction as a 'standard of care' for these disorders is hampered by technical, regulatory and financial concerns. This review identifies some of the major problems and suggests potential solutions. © 2012 Nature America, Inc. All rights reserved. Source

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