Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb?

Francis, Sharon; Raizada, Mohan K.; Mangi, Abeel A.; Melo, Luis G.; Dzau, Victor J.; Vale, Peter R.; Isner, Jeffrey M.; Losordo, Douglas W.; Chao, Julie; Katovich, Michael J.; Berecek, Kathleen H.

doi:10.1152/physiolgenomics.00073.2001

Cited by 24 publications

(18 citation statements)

References 127 publications

(156 reference statements)

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“…It is also an important consideration in the therapy of hypertension to reverse cardiac hypertrophy. 29 In this study, we determined the impact of rAAV Á HK on hypertensive cardiac hypertrophy in SHR. Figure 5 Urine microalbumin levels in SHR.…”

Section: Protection Of Raav á Hk Virus Delivery Against Cardiovasculamentioning

confidence: 99%

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Wang

Zhao

et al. 2004

Gene Ther

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Gene therapy of hypertension requires long-term expression of a therapeutic gene to achieve stable reduction of blood pressure. Human tissue kallikrein (HK) cleaves kininogen to produce a potent vasoactive peptide kinin, which plays an important role in the regulation of the cardiovascular and renal functions. In the present study, we have delivered human kallikrein cDNA with an rAAV vector to explore the potential therapeutic effects of kallikrein on hypertension and related secondary complications. A single tail vein injection of the rAAV-HK vector into the adult spontaneously hypertensive rats resulted in a significant reduction (12.072.55 mmHg, Po0.05, n ¼ 6, ANOVA) of the systolic blood pressure from 2 weeks after vector injection, when compared with the control rAAV-lacZ vector-injected rats. Weekly blood pressure monitoring showed stable hypertension-reduction effect throughout the course of the 20-week experiments. In addition, total urine microalbumin contents decreased as a result of rAAV-HK treatment. Histological analysis of various tissues showed remarkable amelioration of cardiovascular hypertrophy, renal injury and collagen depositions in the rAAV-treated group. Finally, persistent expression of the transgene product HK was confirmed by the enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. We conclude that rAAV-mediated HK delivery rendered a long-term and stable reduction of hypertension and protected against renal injury, cardiac remodeling in the spontaneously hypertensive rat model. Further studies are warranted for the development of a gene therapy strategy for human hypertension.

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Section: Protection Of Raav á Hk Virus Delivery Against Cardiovasculamentioning

confidence: 99%

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Wang

Zhao

et al. 2004

Gene Ther

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“…The gene knockout approach has also run into problems with the failure to produce obvious phenotypes and genomic background effects. 5 The emergence of adenoviral vectors for transient gene therapy 6 and now retroviral vectors to achieve long-term expression of constructs in vivo as described in this study 1 offers a number of advantages for future functional genomics studies. First, viral constructs can be produced to enhance or knockdown the expression of any gene.…”

Section: Gene Therapy Approaches In Hypertension Researchmentioning

confidence: 98%

Gene Therapy and Heme Oxygenase Coming of Age

Roman

2004

Hypertension

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T he article by Yang et al 1 in this issue of Hypertension is noteworthy in that it makes significant contributions in 2 areas. First, the authors describe an approach using retroviral constructs to achieve long-term (up to 5 months) expression of a human heme-oxygenase 1 (HO-1) gene in the liver, kidney, and vasculature of rats in vivo. They also demonstrated that they could knockdown endogenous HO-1 activity in rats by administration of a retrovirus containing a rat HO-1 antisense construct. The second major advance in this study is that it provides new information that further highlights the importance of the HO/CO system as a key modulator of vascular tone in vivo. They found that overexpression of the human HO-1 gene in the rat attenuates the pressor response to intravenous administration of angiotensin II and that knockdown of endogenous HO-1 activity potentiates the pressor response to angiotensin II. Gene Therapy Approaches in Hypertension ResearchThe completion of the sequencing of the human, rat, and mouse genomes now provides an unprecedented opportunity for the discovery of new genes, pathways, and drug targets for the treatment of hypertension and associated end-organ damage. Unfortunately, an examination of the publicly available genome databases (eg, LocusLink, Online Medelian Inheritance in Man [OMIM], the Human Genome Organization [HUGO], and the Genome Database [GDB]) reveals that only Ϸ5000 of the 30 000 predicted human genes have any inferred function. The challenge is now to attach function to the genome and to identify the genes and pathways involved in human disease. Most of the progress to date has been generated using targeted gene knockout in mice. [2][3][4] While this approach has proven to be extremely valuable to confirm the actions of known genes, it has been less effective in defining the function of the newly discovered genes. One of the problems is that it is difficult to develop phenotyping protocols broad enough to identify all the functional consequences associated with knockout of a gene without prior knowledge of the function or organ systems to study. The gene knockout approach has also run into problems with the failure to produce obvious phenotypes and genomic background effects. 5 The emergence of adenoviral vectors for transient gene therapy 6 and now retroviral vectors to achieve long-term expression of constructs in vivo as described in this study 1 offers a number of advantages for future functional genomics studies. First, viral constructs can be produced to enhance or knockdown the expression of any gene. Viral-driven gene therapy can be applied to any species. This is especially relevant to workers using rats, in which a large number of well characterized inbred models of hypertension and associated end-organ damage are available. Given these advantages, it is likely that viral-driven gene therapy approaches as well as other related knockdown techniques (RNAi) will become as commonplace as traditional pharmacological tools to unravel the contribution of different ...

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“…10 In this setting, a full-length or partial cDNA encoding the deficient gene is delivered to the target tissues using a vector system Figure 2. Strategies for genetic manipulation in the cardiovascular system.…”

Section: Strategies For Genetic Manipulation Of the Endotheliummentioning

confidence: 99%

“…Such "gain-of-function" strategies have been used for the overexpression of cytoprotective genes in animal models of vascular and myocardial disease, and in patients with ischemic coronary artery disease. 10,11 In some instances, the short-term inhibition (loss-offunction) of pathogenic genes may be desirable. Acute inhibition of transcription and translation can be achieved by treatment with short single-stranded antisense oligodeoxynucleotides, ribozymes, and, more recently, using RNA interference technology [12][13][14][15] (Figure 2).…”

Section: Strategies For Genetic Manipulation Of the Endotheliummentioning

confidence: 99%

“…The authors observed significant nuclear uptake of the oligonucleotide by the coronary microvascular endothe- Endothelium-targeted genetic manipulation may also be useful for the rescue of ischemic tissues and injured blood vessels (online Table III). 10,11,122 Therapeutic angiogenesis by exogenous supplementation of pro-angiogenic factors such as VEGF and fibroblast growth factor has been proposed as a potential option for treatment of ischemia, particularly in patients for whom percutaneous angioplasty or surgical revascularization has been excluded. 11,123,124 However, several issues remain unresolved regarding the safety and the therapeutic efficacy of angiogenic gene transfer.…”

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confidence: 99%

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Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease

Melo

Gnecchi

Pachori

et al. 2004

ATVB

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Abstract-Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. "Proof-of-concept" for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized. T he vascular endothelium (VE) plays a pivotal role in the regulation of vascular function and homeostasis. 1 In normal conditions, the VE elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation. [2][3][4] Pathological conditions caused by increased oxidative stress, hyperlipidemia, and inflammation lead to endothelial dysfunction, which is characterized by reduced availability of vasodilatory and anti-adhesion substances, such as nitric oxide (NO) and prostacyclin, and concomitant increases in vasoconstrictor and pro-adhesion factors such as endothelin-1, angiotensin II, and thromboxanes 4 (Figure 1). These changes lead to increased vascular tone, inflammatory cell and platelet adhesion, and proliferation of the media smooth muscle, which increase the occurrence of thrombosis and vascular occlusion. 3,4 Because of its central role in the pathogenesis of cardiovascular disease, the endothelium is an attractive therapeutic target for cardiovascular disease. 5 Genetic modulation of endothelial function may offer new opportunities to modify the course of common cardiovascular diseases such as hypertension, atherosclerosis, thrombosis, and ischemic artery disease, whereas the availability of endothelial progenitor cells (EPC) 6 may allow the design of cell-based strategies for rescue of ischemic tissue and rep...

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Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb?

Cited by 24 publications

References 127 publications

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Gene Therapy and Heme Oxygenase Coming of Age

Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease

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