Gene Therapy For Hypertension Research Articles

Gene Therapy for Hypertension, Atherosclerosis, and Familial Hypercholesterolemia: The Old Concepts and the New Era

Cardiovascular disease remains the main cause of mortality in the 21st century. Hypertension, vessel atherosclerosis, and familial hypercholesterolemia (FH) are responsible for increased mortality and morbidity in patients. Therapies for cardiovascular disease are based on drug treatment options, but in the era of precision medicine, personalized treatments are being developed. Studies have shown that these conditions have a strong genetic background, creating an opportunity for the implementation of gene therapy for these diseases. Currently, gene therapy is not widely used in clinical practice. Recent advances in this research field are making gene therapy a very promising preventive and therapeutic tool for cardiovascular disease. Essential hypertension’s (EH) pathophysiology is mostly based on the activation of both the sympathetic nervous system and the renin angiotensin aldosterone system (RAAS), natriuretic peptide production, and endothelial dysfunction. Plasmid DNA and viral vectors can be used, targeting the main mechanisms in the pathogenesis of EH. Many preclinical studies have been developed across the years, presenting a significant decrease in blood pressure. Nevertheless, no clinical studies have been developed studying the implementation of gene therapy in EH. Atherosclerotic damage is caused by monogenic diseases or is deteriorated by the activation of inflammation in the vessel wall. Gene therapy studies have been developed in the pre- and clinical phases targeting the lipoprotein and cholesterol metabolism and the inflammation of the vessels. FH is a common inherited metabolic disease associated with high levels of cholesterol in the blood. Clinical trials of gene therapy have been developed and presented optimistic results. In this review, the challenges of gene therapy for cardiovascular disease are outlined. Nevertheless, more clinical trials are needed to be performed for the development of convenient and safe drug schemes for our patients.

Gene therapy for hypertension: focus on zilebesiran

Gene therapy for hypertension: focus on zilebesiran

Historical Archive of Blood Pressure and Evolution of Hypertension

Blood pressure is the pressure of the blood within the arteries of the circulatory system. The pulse is the feeling of the heartbeat in some arteries. Hypertension also known as high blood pressure, is the name given to a common medical condition in which the force exerted by the blood carried from the heart to the body against the walls of the arteries is high enough to cause health problems such as heart disease. Hypertension has been known since antiquity. Descriptions have been found in the Egyptian papyri, in ancient Chinese and Indian medical literature, as well as, in the work of ancient Greek physicians such as Galen and Hippocrates and Muslim scientists into Latin in Andalusia and Sicily. When we come to the 17th century, we see that blood circulation was experimentally proven by William Harvey. The important work of the 18th century, blood pressure was first recognized and first attempts were made to measure this pressure. The clinical sphygmomanometer that could measure systolic pressure over the radial artery is defined by Samuel von Basch in 1880. 20th century has witnessed changes in terminology, discovery of the measurement method that is recently used and emergence of pathogenetic definitions and by the middle of the twentieth century, checking BP by sphygmomanometer became part of the routine physical examination in hospitals and clinics. It was considered necessary to treat hypertension after the detrimental effects of high blood pressure on the body were noticed. So reserpine, hydralazine, ganglion blocking agents, peripheral adrenergic inhibitor, oral diuretics, beta blocker, ACE inhibitors, calcium channel blockers drugs such as were synthesized. While the use of some drugs is limited due to their side effects, some are still used in the treatment of hypertension today. Additionally the potential for gene therapy in hypertension is one that will be watched with interest.The search for new antihypertensive drugs are still ongoing. The potential for gene therapy in hypertension is one that will be watched with interest.
 Keywords: History of blood pressure, pulse, hypertension, antihypertensive drugs

Epigenetic Control of Hypertension by DNA Methylation: A Real Possibility

Hypertension is a common chronic disease that particularly affects the elderly and can trigger several cardiovascular conditions. Although the treatment of hypertension has evolved in recent decades, many hypertensive patients still do not have properly controlled blood pressure. Accumulating evidence supports the hypothesis that DNA methylation plays an important role in regulating gene expression, altering the phenotype and function of the cardiovascular system. The present review highlights recent advances in research on DNA methylation in the development of hypertension. Several preclinical and clinical evidence show that methylation of different targets appears to be involved in hypertension. Studies of the involvement of DNA methylation have greatly improved our understanding of hypertension, but its use as a valid therapeutic target is still unknown. Further studies could help to bring to light the truth about gene therapy in hypertension.

Toward Gene Therapy of Hypertension: Experimental Study on Hypertensive ISIAH Rats.

TiO2-based nanocomposites were prepared to deliver oligonucleotides into cells. The nanocomposites were designed by the immobilization of polylysine-containing oligonucleotides on TiO2-nanoparticles (TiO2·PL-DNA). We showed for the first time the possibility of using the proposed nanocomposites for treatment of hypertensive disease by introducing them into hypertensive ISIAH rats developed as a model of stress-sensitive arterial hypertension. The mRNA of the gene encoding angiotensin I-converting enzyme (ACE1) involved in the synthesis of angiotensin II was chosen as a target. Administration (intraperitoneal injection and inhalation) of the nanocomposite showed a significant (by 20-30mm Hg) decrease in systolic blood pressure when the nanocomposite contained the ACE1 gene-targeted oligonucleotide. When using the oligonucleotide with a random sequence, no effect was observed. Further development and improvement of the inhalation nanocomposite drug delivery to systemic hypertensive disease treatment promises new possibilities for clinical practice.

Effects of RNA interference targeting angiotensin 1a receptor on blood pressure and cardiac hypertrophy of rats with renovascular hypertension

The aim of this study is to investigate the effects of RNA interference (RNAi) targeting angiotensin 1a receptor (AT1a) on blood pressure and cardiac hypertrophy of rats with renovascular hypertension. Two RNAi plasmids, pAT1a-shRNA1 and pAT1a-shRNA2 each carrying a U6 promoter and an AT1a-specific shRNA-coding template sequence corresponding to the sites 928–946, 978–996 of the mRNA transcript, and a control plasmid pCon carrying a nonspecific shRNA-coding sequence were constructed. Thirty Sprague — Dawley rats with renovascular hypertension (2-kidney 1-clip) were randomly divided into 5 equal groups: Control group (without any intervention), pAT1a-shRNA1, pAT1a-shRNA2, pCon groups (with injection of the corresponding plasmid 4 mg/kg respectively into the tail vein), and valsartan group (30 mg/kg·d−1 by gavage). Three weeks after drug administration, pAT1a-shRNA1, pAT1a-shRNA2 and valsartan respectively resulted in decrease of the tail blood pressure by (15.1 ± 5.4), (16.4 ± 8.4) and (30.6 ± 18.2) mmHg. However, the tail blood pressure increased further by about 25 mmHg in both of pCon and control groups. The carotid artery pressures of pAT1a-shRNA1, pAT1a-shRNA2 and valsartan groups were all significantly lower than those of the control and pCon groups. The ratio of left ventricle weight to body weight (LV/BW) of the rats in pAT1a-shRNA1, pAT1a-shRNA2, and valsartan groups decreased significantly than in the control group (P 0.05). Histopathological examination showed that the myocardiocytes were significantly hypertrophic and the basal membrane of the aorta was significantly thickened in the control group and such changes were alleviated in the pAT1a-shRNA1, pAT1a-shRNA2 and valsartan groups. Compared with the control group, pAT1a-shRNA1 and pAT1a-shRNA2 groups had lowered expression of AT1 receptor (in the myocardium and the thoracic aorta (all P 0.05). We conclude that RNAi targeting AT1a receptor inhibits the development of renovascular hypertension and the accompanying cardiac hypertrophy. RNAi technology may become a new strategy of gene therapy for hypertension.

Intramuscular delivery of rAAV-mediated kallikrein gene reduces hypertension and prevents cardiovascular injuries in model rats

The overexpression of the human tissue kallikrein (HK) gene can reduce blood pressure and ameliorate the secondary syndromes associated with hypertension in animal models. The current study was designed to investigate hypotensive effect of intramuscular delivery of HK gene. We generated an recombinant adeno-associated virus (rAAV) vector expressing human tissue kallikrein under the control of a cytomegalovirus promoter and administered the rAAV-HK vector to a spontaneously hypertensive rat model at a dose of 1 x 10(10) virons/rat through intramuscular injection. A persistent, high-level expression of HK post-gene delivery was confirmed by ELISA. The systolic blood pressure in the rats receiving rAAV-LacZ and saline increased from 171.3 mmHg to 182.3 mmHg 28 weeks' post injection. In contrast, the delivery of the HK gene by AAV vectors attenuated the increase of the systolic blood pressure in the treated group. The systolic blood pressure was only slightly lowered (from a level of 174 mmHg to 170.5 mmHg) post-vector administration. The difference in blood pressure between the treated group and the control groups is statistically significant at 12.6 mmHg. The hypotensive effect of rAAV-HK persisted until the end of the testing period. In addition, a significant amelioration of cardiovascular hypertrophy, renal injury, and collagen depositions in the rAAV-HK-treated animals were also observed. All the effects are comparable with those of intravenous delivery. Therefore, the intramuscular administration of rAAV-HK may be used in gene therapy for hypertension.

Effects of RNA interference targeting angiotensin 1a receptor on the blood pressure and cardiac hypertrophy of rats with 2K1C hypertension

To investigate the effects of RNA interference (RNAi) targeting angiotensin 1a (AT1a) receptor on the blood pressure and cardiac hypertrophy of rats with 2K1C (2-kidney, 1-clip) hypertension. Two kinds of RNAi plasmids, pAT1a-shRNA1 carrying an U6 promoter and an AT1a-specific shRNA-coding template sequence corresponding the sites 928 - 946 and pAT1a-shRNA2 carrying an U6 promoter and an AT1a-specific shRNA-coding template sequence corresponding the sites 978 - 996, and a blank plasmid pCon carrying a nonspecific shRNA-coding sequence were constructed. Thirty Sprague-Dawley rats underwent clipping of the left renal artery so as to establish two-kidney, one-clip (2K1C) hypertension models and then were randomly divided into 5 equal groups: pAT1a-shRNA1 group (injected with pAT1a-shRNA1 4 mg/kg only one time), pAT1a-shRNA2 group (injected with pAT1a-shRNA2 4 mg/kg only one time), pCon group (injected with pCon 4 mg/kg only one time), valsartan group (perfused into the stomach with valsartan, a AT1 receptor inhibitor 30 mg.kg(-1).d(-1), for 3 weeks), and control blank group (without any treatment). Three weeks later, the systolic pressure of the caudal artery was measured, catheterization through carotid artery was conducted to measure the systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the left ventricular pressure curve was drawn. Then the rats were killed; the weight of the heart was measured, the ratio of left ventricle weight to body weight (LV/BW) was calculated, and pathological examination of the heart and thoracic aorta was performed. Western blotting was used to detect the protein expression of AT21 in the ventricle and aorta. Six age-matched healthy rats were used as normal controls. There was no significant difference in the caudal artery pressure among the 5 groups (all P > 0.05) before intervention. Three weeks later the caudal artery pressures of the blank control group and pCon group continued to significantly increase by about 25 mm Hg compared to the values before the intervention (both P < 0.001) and without significant difference between these 2 groups; however, the caudal artery pressures of the pAT1a-shRNA1, pAT1a-shRNA2, and valsartan groups were 15.1 mm Hg +/- 5.4 mm Hg, 16.4 mm Hg +/- 8.4 mm Hg, and 30.6 mm Hg +/- 18.2 mm Hg lower than those before the intervention respectively (all P < 0.01); and were also significantly lower than those of the blank groups (P < 0.01 or P < 0.05). There was no significant differences in the +/- dp/dt value and indicators of renal function among these groups. The carotid artery pressure of the pAT1a-shRNA1, pAT1a-shRNA2, and valsartan groups were 194 mm Hg +/- 5 mm Hg, 200 mm Hg +/- 5 mm Hg, and 164 mm Hg +/- 5 mm Hg, all significantly lower than those of the blank and pCon groups (234 mm Hg +/- 10 mm Hg and 232 mm Hg +/- 7 mm Hg respectively, all P < 0.01). The LV/BW of the pAT1a-shRNA1, pAT1a-shRNA2, and valsartan groups were 2.27 +/- 0.37, 2.31 +/- 0.26, and 2.26 +/- 0.39, all significantly lower than that of the blank and pCon groups (3.24 +/- 0.38 and 2.94 +/- 0.06, respectively, all P < 0.01), similar to that of the normal control group (P > 0.05). The myocardiocytes were significantly hypertrophic and the arterial tunica media was significantly thickened in the blank group and such changes were all improved to different degrees in the pAT1a-shRNA1, pAT1a-shRNA2, and valsartan groups. The protein expression levels of AT1 receptor in the myocardium of the pAT1a-shRNA and pAT1a-shRNA2 groups were lower by 53.3% and 47.8% respectively than that of the blank group, and the protein expression levels of AT1 receptor in the thoracic aorta of the pAT1a-shRNA and pAT1a-shRNA2 groups were lower by 58.7% and 49.3% respectively than that of the blank group (all P < 0.01); however, there were no significant difference in the protein expression levels of AT1 receptor in the myocardium and thoracic aorta between the valsartan and blank groups (both P > 0.05). RNA interference targeting AT1a receptor inhibits the development of renovascular hypertension and the accompanying cardiac hypertrophy. The RNAi technology may become a new strategy of gene therapy for hypertension.

Potential of Gene Therapy Strategy for the Treatment of Hypertension

Hypertension is one of the most important risk factors for cardiovascular diseases (CVDs). CVD extends across all populations and represents the leading cause of morbidity and mortality in industrialized countries. Hypertension increases the risk of peripheral arterial disease, cardiomyopathy, stroke, and renal failure. The disease affects &50 million Americans and goes undetected in at least one third of the population. In spite of the tremendous progress made by pharmacotherapy in the management and control of hypertension, there has been a steady escalation in its prevalence during the last decade. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau and that novel and innovative approaches must be sought for the treatment, control, and possible cure of hypertension. As a result, efforts of our group and those of many others have been diverted to explore the use of gene transfer and gene therapy strategies for a long-term control of hypertension. We have argued that gene therapy offers potentially significant improvements and benefits over the use of traditional pharmacotherapy: (1) noncompliance by patients can be significantly reduced or even eliminated because of the fact that a single treatment involving gene transfer could remain effective for months or even years; (2) side effects associated with pharmacotherapy can be minimized as a result of specific targeting of a therapeutic gene in a given tissue and optimally influencing cardiovascular pathophysiology on an individual patient basis; and (3) with its potential to produce long-term beneficial outcomes in end-organ damage, the gene therapy strategy could lead to a cure of hypertension and its related pathophysiology. It is noteworthy to mention that current pharmacotherapies are often unable to reverse end-organ damage associated with hypertension. In order for the gene therapy for hypertension to be successful, one must provide conceptual support of its efficacy in …

1] Gene therapy for hypertension: The preclinical data

In spite of several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly due to the fact that all available drugs are short-lasting (24 hr or less), have side effects, and are not highly specific. Gene therapy offers the possibility of producing longer-lasting effects with precise specificity from the genetic design. Preclinical studies on gene therapy for hypertension have taken two approaches. Chao et al. have carried out extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin nitric oxide synthase into different rat models. Their results show that blood pressure can be lowered for 3-12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the beta 1-adrenoceptor, TRH, angiotensin gene activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been two methods of delivery antisense; one is short oligodeoxynucleotides, and the other is full-length DNA in viral vectors. All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligonucleotides are safe and nontoxic. The adeno-associated virus delivery antisense to AT1 receptors is systemic and in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to Phase I trials for testing the antisense ODNs, first and later the AAV.

Gene therapy for hypertension: the preclinical data.

Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting (</=24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on gene therapy for hypertension have taken 2 approaches. Chao et al have performed extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin NO synthase into different rat models. Their results show that blood pressure can be lowered for 3 to 12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 (AT(1)) receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the beta(1)-adrenoceptor, thyrotropin-releasing hormone, angiotensin gene-activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been 2 methods of delivering antisense: one is by oligodeoxynucleotides, and the other is with full-length DNA in viral vectors. All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligos are safe and nontoxic and could be delivered orally or eventually by skin patches. Systemic delivery of recombinant adeno-associated virus with DNA antisense to AT(1) receptors in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to phase I trials for testing some of the antisense oligodeoxynucleotides, although testing the viral vectors needs much more work.

Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium.

The use of viral vectors for vascular gene therapy targeted at the endothelium is limited by the promiscuous tropism of vectors and nonspecificity of viral promoters, resulting in high-level transgene expression in multiple tissues. To evaluate suitable endothelial cell (EC)-specific promoters for vascular gene therapy, we directly compared the ability of the fms-like tyrosine kinase-1 (FLT-1), intercellular adhesion molecule-2 (ICAM-2), and von Willebrand factor (vWF) promoters to drive EC-restricted transcription after cloning into adenoviral vectors upstream of lacZ. Vastly different expression profiles were observed. Whereas both FLT-1 and ICAM-2 promoters generated transgene expression levels similar to cytomegalovirus in ECs in vitro, vWF expression levels were extremely low. Analysis of non-EC types revealed that ICAM-2 but not FLT-1 evoked leaky transgene expression, thus identifying FLT-1 as the most selective promoter. With an ex vivo human gene therapy model, the FLT-1 promoter demonstrated EC-specific transgene expression in intact human vein but no detectable expression from infected exposed smooth muscle cells in EC-denuded vein. Furthermore, when adenoviruses were systemically administered to mice, the FLT-1 promoter demonstrated extremely low-level gene expression in the liver, the major target organ for adenoviral transduction in vivo. This study highlights the potential of using the FLT-1 promoter for local and systemic human gene therapy in hypertension and its complications.

Somatic gene therapy for hypertension with adeno-associated delivery of antisense to angiotensin type 1 receptor mRNA

Somatic gene therapy for hypertension with adeno-associated delivery of antisense to angiotensin type 1 receptor mRNA

Targeting Gene Transfer Selectively to Vascular Endothelial Cells Using Peptides Isolated by Phage Display: Implications for Development of Gene Therapy in Hypertension

75 Current gene transfer vectors are extremely limited for selective vascular cell delivery due to their promiscuous tropism and low efficiency of gene delivery to the vasculature. We have sought to improve the efficiency of gene transfer to vascular endothelial cells using phage display. Using bio-panning on whole cells, we have isolated a panel of 60 7-mer peptides that have the ability to bind endothelial cells but not to non-endothelial cells including vascular smooth muscle cells and hepatocytes. One candidate peptide was cloned upstream of a single chain antibody (scFv) generated against the knob domain of adenovirus type 5, expressed in bacteria and purified. While the scFv alone inhibited adenoviral fiber-dependent infection of all cell types tested (to &gt;95% in hepatocytes), the scFv-peptide fusion mediated selective infection into endothelial cells without infection into non-endothelial cells types. Furthermore, the level of infection achieved in endothelial cells was 15 fold higher than that achieved with fiber-mediated gene transfer alone. We have additionally isolated 15 individual peptides that have the ability to target the endothelial leptin-like oxidised LDL receptor (LOX-1), a receptor highly expressed in endothelial cells in hypertensive models and in atherosclerotic lesions, by phage bio-panning on cells ectopically expressing the LOX-1 receptor. Candidate peptides mediated significantly higher binding to LOX-1 expressing cells compared to LOX-1 negative cells. Their ability to re-target adenoviral gene transfer is being tested. Our results demonstrate that small, novel peptides isolated by phage display have the ability to retarget gene transfer selectively and efficiently to vascular endothelial cells. This has important implications for targeting gene transfer to endothelial cells for molecular and therapeutic protocols in hypertension.

Targeting Gene Transfer Selectively to Vascular Endothelial Cells Using Peptides Isolated by Phage Display: Implications for Development of Gene Therapy in Hypertension

75 Current gene transfer vectors are extremely limited for selective vascular cell delivery due to their promiscuous tropism and low efficiency of gene delivery to the vasculature. We have sought to improve the efficiency of gene transfer to vascular endothelial cells using phage display. Using bio-panning on whole cells, we have isolated a panel of 60 7-mer peptides that have the ability to bind endothelial cells but not to non-endothelial cells including vascular smooth muscle cells and hepatocytes. One candidate peptide was cloned upstream of a single chain antibody (scFv) generated against the knob domain of adenovirus type 5, expressed in bacteria and purified. While the scFv alone inhibited adenoviral fiber-dependent infection of all cell types tested (to >95% in hepatocytes), the scFv-peptide fusion mediated selective infection into endothelial cells without infection into non-endothelial cells types. Furthermore, the level of infection achieved in endothelial cells was 15 fold higher than that achieved with fiber-mediated gene transfer alone. We have additionally isolated 15 individual peptides that have the ability to target the endothelial leptin-like oxidised LDL receptor (LOX-1), a receptor highly expressed in endothelial cells in hypertensive models and in atherosclerotic lesions, by phage bio-panning on cells ectopically expressing the LOX-1 receptor. Candidate peptides mediated significantly higher binding to LOX-1 expressing cells compared to LOX-1 negative cells. Their ability to re-target adenoviral gene transfer is being tested. Our results demonstrate that small, novel peptides isolated by phage display have the ability to retarget gene transfer selectively and efficiently to vascular endothelial cells. This has important implications for targeting gene transfer to endothelial cells for molecular and therapeutic protocols in hypertension.

Gene Therapy for Hypertension: Recombinant Adeno-Associated Virus Vector Delivery of Angiotensin Type 1 Receptor Antisense in Hypertensive Double Transgenic Mice

P204 Introduction: The goal of gene therapy for hypertension is to produce prolonged reductions of high blood pressure with a single administration of a transgene. We have developed gene therapy using adeno-associated virus (AAV)antisense (AS) as a vector because it is safe, stable and effective. However, because large quantities of AAV are not yet available, our previous studies were in baby rats or by brain injections to achieve an effective concentration of AAV. Since mice are one-tenth the size of rats, systemic injection of AAV-AS achieves higher concentrations than in rats. To test systemic injection in an adult hypertensive model, this study uses double transgenic (dt) mice, with human renin (hR) and human AGT (hAGT) transgenes. In these mice, plasma Ang II levels are elevated and blood pressure increased (∼156 mmHg), compared to controls (∼ 100 mmHg). Methods: dt mice with established baseline BP of >156 mmHg (n=5) were injected (100 μl) with a single dose of 4x1010 infectious particles of rAAV-AT1R-AS. Blood pressure recordings by the tailcuff method were made once per week for 6 months. Results: One week after intracardiac injection of rAAV-AT1R-AS, blood pressure decreased by 35-50 mmHg (p<0.01,compared to baseline). The normalized blood pressure persisted for the full length of the study, 28 weeks. Individual mice were sacrificed at 14-28 weeks and tissues taken for detection of rAAV-AT1R- AS, At both time periods, the neor transgene was present in lung, kidney, liver, heart, adrenal gland and fat. The rAAV was not detected in the brain. Renal arterioles (n=3) showed a reduced (50%)contractile response to doses of Ang II, compared to controls (n=3). Conclusion: The results demonstrated that a single systemic delivery of rAAV-AT1R-AS in adult, hypertensive mice produces a profound decrease in blood pressure for at least 6 months. The prolonged effect is due to the continuous expression of the AT1-R antisense transgene inhibiting AT1 receptors.

Gene Therapy for Hypertension

Somatic gene delivery approaches have received wide attention as a new technique for studying gene expression and as a potential therapeutic tool in treating both inherited and acquired diseases. Recent studies using nonviral and viral vectors have shown great promise for gene therapy in hypertensive diseases. Potential targets for prospective gene therapy in hypertension include vasopressor renin-angiotensin system components and a number of vasodilator polypeptides such as tissue kallikrein-kinin, atrial natriuretic peptide, adrenomedullin and nitric oxide synthase. Antisense inhibition with oligonucleotides or cDNAs encoding renin, angiotensinogen, angiotensin-converting enzyme and angiotensin receptors has been shown to cause a prolonged blood pressure reduction in spontaneously hypertensive rats. To evaluate the therapeutic potential of vasodilator proteins or peptides in high blood pressure, we delivered the genes encoding human tissue kallikrein, atrial natriuretic peptide, nitric oxide synthase, and adrenomedullin into hypertensive rat models and showed that a single injection resulted in a significant and sustained reduction of blood pressure for several weeks. The potency and duration of blood pressure reduction depends on the dose and the promoter of the gene administered, age and sex of the hypertensive animals as well as the vehicle used for gene delivery. Somatic gene transfer of human tissue kallikrein or atrial natriuretic peptide not only attenuated hypertension but also exerted a protective effect against salt-induced renal damage and cardiac hypertrophy in Dahl salt-sensitive rats after high salt loading. These results suggest that the application of antisense inhibition of vasopressors, or gene delivery of vasodepressors for gene therapy, may have potential in treating human hypertension, and cardiovascular and renal disorders.

Gene therapy for hypertension

Gene therapy for hypertension

Gene therapy for hypertension: Antisense inhibition with adeno-associated viral vector delivery targeting angiotensin II type 1-receptor messenger ribonucleic acid

Gene therapy for hypertension: Antisense inhibition with adeno-associated viral vector delivery targeting angiotensin II type 1-receptor messenger ribonucleic acid

Gene Therapy in Hypertension: Adenovirus-Mediated Kallikrein Gene Delivery in Hypertensive Rats

Tissue kallikrein has been shown to play a role in blood pressure regulation, and abnormalities in the kallikreinkinin system are considered to be a factor in the pathogenesis of hypertension. To elucidate the potential therapeutic effects of kallikrein gene delivery in hypertension, an adenoviral vector containing the human tissue kallikrein gene under the control of a cytomegalovirus promoter, Ad.CMV-cHK, was intravenously injected into spontaneously hypertensive rats (SHR). A single injection of Ad.CMV-cHK into SHR caused a sustained delay in the increase in blood pressure from day 2 to day 41 post injection, as compared to control rats receiving Ad.CMV-LacZ adenovirus. Adenovirus-mediated kallikrein gene delivery had no effect on the blood pressure of normotensive Wistar-Kyoto rats. Human tissue kallikrein mRNA was detected in the liver, kidney, spleen, adrenal gland, and aorta. Immunoreactive human tissue kallikrein can be detected in sera and urine of rats receiving kallikrein gene delivery. Human tissue kallikrein in rat serum was at the highest level 5 days post injection, and the level declined gradually. Urinary kinin and cGMP levels were significantly increased in rats receiving kallikrein gene delivery compared to Ad.CMV-LacZ control rats. These results show that adenovirus-mediated delivery of human tissue kallikrein results in high-efficiency expression and blood pressure reduction in SHR. Application of adenovirus-mediated systemic expression of the tissue kallikrein gene may provide a unique way of delivering the gene product into the vasculature and could have important therapeutic implications in treating hypertension.