RNA Interference: A Potent Tool for Gene-Specific Therapeutics

Ichim, Thomas E.; Li, Mu; Qian, Hua; Popov, Igor; Rycerz, Katarzyna; Zheng, Xiufen; White, David G.; Zhong, Robert; Min, Wei‐Ping

doi:10.1111/j.1600-6143.2004.00530.x

Cited by 84 publications

(63 citation statements)

References 96 publications

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“…Thus, the use of hVDAC1-shRNA to interfere with VDAC1 expression constitutes a potential therapeutic measure for inhibiting cell growth. Recently, the therapeutic potential of siRNA has been recognized, particularly in areas of infectious diseases and cancer (34,35). Silencing of Bcl-2 induced massive p53-dependent apoptosis (36), and reducing the level of the androgen receptor in prostate cancer cells led to apoptosis by disrupting the Bcl-xL-mediated survival signal (37).…”

Section: Discussionmentioning

confidence: 99%

The expression level of the voltage-dependent anion channel controls life and death of the cell

Abu-Hamad

Sivan

Shoshan‐Barmatz

2006

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

221

249

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Mitochondria not only generate cellular energy, but also act as the point for cellular decisions leading to apoptosis. The voltage-dependent anion channel (VDAC), as a major mitochondrial outer-membrane transporter, has an important role in energy production by controlling metabolite traffic and is also recognized as a key protein in mitochondria-mediated apoptosis. In this study, the role of VDAC1 in regulating cell survival and death was investigated by silencing endogenous human (h)VDAC1 expression by using a short hairpin RNA (shRNA)-expressing vector. The shRNA effectively down-regulated the expression in human T-REx-293 cells of hVDAC1 but not murine (m)VDAC1. Cells in which hVDAC1 expression was decreased by ≈90% proliferated extremely slowly. Normal growth was, however, restored upon expression of mVDAC1 in a tetracycline-regulated manner. Although low tetracycline concentrations promoted cell growth, high concentrations induced mVDAC1 overexpression, leading to cell death. Cells with low levels of VDAC1 showed 4-fold-lower ATP-synthesis capacity and contained low ATP and ADP levels, with a strong correlation between ATP levels and cell growth, suggesting limited metabolite exchange between mitochondria and cytosol. The possibility of suppressing endogenous hVDAC1 expression and introducing native and mutated mVDAC1 is used to further explore the involvement of VDAC1 in apoptosis. Cells suppressed for hVDAC1 but expressing either native mVDAC1 or an E72Q mutant underwent apoptosis induced by various stimuli that can be inhibited by ruthenium red in the native cells but not in the mutated cells, suggesting that VDAC1 regulates apoptosis independent of the apoptosis-inducing pathway.

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Section: Discussionmentioning

confidence: 99%

The expression level of the voltage-dependent anion channel controls life and death of the cell

Abu-Hamad

Sivan

Shoshan‐Barmatz

2006

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

221

249

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“…Consequently, there is a great need for a more potent and physiologically acceptable method of specifically blocking gene expression. siRNA would be an ideal approach, owing to its potency, specificity, simplicity, and relative safety (56,57). We previously have silenced DC using siRNA to achieve immune modulation (23,56,58).…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation and Tolerance Induction by RelB-Silenced Dendritic Cells through RNA Interference

Zhang

Zheng

Lian

et al. 2007

The Journal of Immunology

Self Cite

118

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Dendritic cells (DC), the most potent APCs, can initiate the immune response or help induce immune tolerance, depending upon their level of maturation. DC maturation is associated with activation of the NF-κB pathway, and the primary NF-κB protein involved in DC maturation is RelB, which coordinates RelA/p50-mediated DC differentiation. In this study, we show that silencing RelB using small interfering RNA results in arrest of DC maturation with reduced expression of the MHC class II, CD80, and CD86. Functionally, RelB-silenced DC inhibited MLR, and inhibitory effects on alloreactive immune responses were in an Ag-specific fashion. RelB-silenced DC also displayed strong in vivo immune regulation. An inhibited Ag-specific response was seen after immunization with keyhole limpet hemocyanin-pulsed and RelB-silenced DC, due to the expansion of T regulatory cells. Administration of donor-derived RelB-silenced DC significantly prevented allograft rejection in murine heart transplantation. This study demonstrates for the first time that transplant tolerance can be induced by means of RNA interference using in vitro-generated tolerogenic DC.

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“…They may also be introduced directly to the donor organ in preservation fluid prior to transplantation previously described in a murine model [35,115,116]. This approach has also used antisense oligonucleotides [116] however, high concentrations of this agent are required to induce an effect.…”

Section: Small Interfering Rnas (Sirnas)mentioning

confidence: 99%

Complement—here, there and everywhere, but what about the transplanted organ?

Montero

Sacks

Smith

2016

Seminars in Immunology

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The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed "complement" by Ehrlich to reflect its complementarity to antibodies having previously been described as "alexine" (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ.We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment. Word count 169

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RNA Interference: A Potent Tool for Gene-Specific Therapeutics

Cited by 84 publications

References 96 publications

The expression level of the voltage-dependent anion channel controls life and death of the cell

The expression level of the voltage-dependent anion channel controls life and death of the cell

Immune Modulation and Tolerance Induction by RelB-Silenced Dendritic Cells through RNA Interference

Complement—here, there and everywhere, but what about the transplanted organ?

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