Drug-gene interaction between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and antihypertensive therapy

BACKGROUND: Despite the availability of a variety of effective drugs, inadequate control of blood pressure is common. There are some indications that the angiotensin-converting enzyme (ACE) gene modifies the response to antihypertensive drugs, but the results have been inconclusive. OBJECTIVE: To investigate whether the insertion/deletion polymorphism of the ACE gene modifies blood pressure differences among subjects using diuretics, beta-blockers, calcium-channel antagonists, or ACE inhibitors. METHODS: Data were used from the Rotterdam Study, a population-based, prospective, cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or older. Data from 3 subsequent cross-sectional investigations were used, as well. Subjects were included if they had high blood pressure during one or more examinations and/or used monotherapy with a diuretic, beta-blocker, calcium-channel antagonist, or ACE inhibitor. A marginal, generalized, linear model was used to assess the association between the mean difference in systolic/diastolic blood pressure and antihypertensive classes stratified by the 3 genotypes. RESULTS: In total, 3025 hypertensive individuals were included, and 6500 measurements of blood pressure were taken. The percentages of DD, ID, and II genotypes were 28.3%, 51.4%, and 20.3%, respectively. The mean differences in systolic blood pressure between the II and DD genotypes were 0.23 mm Hg (95% CI -5.48 to 5.94) for diuretics, -2.41 mm Hg (95% CI -6.72 to 1.90) for beta-blockers, 2.12 mm Hg (95% CI -4.64 to 8.89) for calcium-channel antagonists, and -2.01 mm Hg (95% CI -9.82 to 5.79) for ACE inhibitors. CONCLUSIONS: The adjusted mean difference in diastolic and systolic blood pressure among diuretic, beta-blocker, calcium-channel antagonist, or ACE inhibitor users was not modified by the ACE insertion/deletion polymorphism.     

The ethics of gene therapy

Recent developments have progressed in areas of science that pertain to gene therapy and its ethical implications. This review discusses the current state of therapeutic gene technologies, including stem cell therapies and genetic modification, and identifies ethical issues of concern in relation to the science of gene therapy and its application, including the ethics of embryonic stem cell research and therapeutic cloning, the risks associated with gene therapy, and the ethics of clinical research in developing new therapeutic technologies. Additionally, ethical issues relating to genetic modification itself are considered: the significance of the human genome, the distinction between therapy and enhancement, and concerns regarding gene therapy as a eugenic practice.     

The evolving concept of gene therapy

The use of molecular techniques to correct human genetic diseases is a concept that was considered extremely remote by many investigators until quite recently. Several factors were responsible for changing the scientific community's attitude toward gene therapy: the development of recombinant DNA technology including the ability to clone disease-related genes; maturation of scientific and ethical reflection following apparent failures of early human experiments; and the development of efficient techniques for the transfer of genes into mammalian cells. Now is the time for the scientific and medical communities to come together and to cooperate to make human gene therapy a clinically useful procedure.     

The continuing contribution of gene marking to cell and gene therapy.

Gene-marking studies were the first gene-transfer protocols approved for human use. Their intent was not directly therapeutic but rather to track the behavior and fate of cells in vivo, and to use this information to improve treatment protocols. For more than fifteen years, gene-marking studies using retroviral vectors have provided invaluable information about the biology of human hematopoietic cells and T lymphocytes, and have helped guide cell therapies intended to treat malignant disease. Although the safety record of marking studies has been impeccable, the development of leukemia by immunodeficient children treated with retroviral vectors cast a pall over the entire field and essentially brought the era of pure gene-marking studies to an abrupt end. Paradoxically, the impetus these events gave to studying retroviral integration sites in host cell DNA emphasized the additional information that marker studies could provide about the behavior of cells at the clonal level. As confidence has slowly returned, marker studies have reappeared, usually as components of gene therapy protocols in which a marker gene or sequence is incorporated to allow the modified cells to be tracked or imaged in vivo. Hence, gene marking continues to have much to offer in terms of our understanding of the behavior, fate, and safety of gene-modified cells in vivo.     

Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors

Increasing evidence reveals that random insertion of gene transfer vectors into the genome of repopulating hematopoietic cells may alter their fate in vivo. Although most insertional mutations are expected to have few if any consequences for cellular survival, clonal dominance caused by retroviral vector insertions in (or in the vicinity of) proto-oncogenes or other signaling genes has been described for both normal and malignant hematopoiesis. Important insights into these side effects were initially obtained in murine models. Results from ongoing clinical studies have revealed that similar adverse events may also occur in human gene therapy. However, it remains unknown to what extent the outcome of insertional mutagenesis induced by gene vectors is related to (1) the architecture and type of vector used, (2) intrinsic properties of the target cell, and (3) extrinsic and potentially disease-specific factors influencing clonal competition in vivo. This review discusses reports addressing these questions, underlining the need for models that demonstrate and quantify the functional consequences of insertional mutagenesis. Improving vector design appears to be the most straightforward approach to increase safety, provided all relevant cofactors are considered.     

The clinical potential of antiepileptic gene therapy

Epilepsy afflicts approximately 1% of the population and, although the majority of patients gain effective seizure control through existing medications, a significant number prove refractory to treatment. For intractable focal epilepsies, gene therapy techniques provide a realistic treatment alternative, especially in patients who are considered surgical candidates. Neurotransmitter receptors and ion channels offer attractive gene therapy targets, but the pattern of viral vector transduction and gene expression can dramatically influence the final outcome. Recently, studies have shown that viral vector-mediated transduction and expression of neuroactive peptides, such as galanin and neuropeptide Y, can attenuate seizure sensitivity and prevent seizure-induced cell death in vivo. As future studies define the best means to avoid immunological silencing, as well as establish transduction properties in pathological, epileptic tissue, it should be possible to develop an efficacious gene therapy for intractable focal epilepsy.     

The clinical potential of antiepileptic gene therapy

Epilepsy afflicts ～ 1% of the population and, although the majority of patients gain effective seizure control through existing medications, a significant number prove refractory to treatment. For intractable focal epilepsies, gene therapy techniques provide a realistic treatment alternative, especially in patients who are considered surgical candidates. Neurotransmitter receptors and ion channels offer attractive gene therapy targets, but the pattern of viral vector transduction and gene expression can dramatically influence the final outcome. Recently, studies have shown that viral vector-mediated transduction and expression of neuroactive peptides, such as galanin and neuropeptide Y, can attenuate seizure sensitivity and prevent seizure-induced cell death in vivo. As future studies define the best means to avoid immunological silencing, as well as establish transduction properties in pathological, epileptic tissue, it should be possible to develop an efficacious gene therapy for intractable focal epilepsy.     

脑卒中患者血管紧张素转化酶基因插入/缺失多态性分析

目的 探讨血管紧张素转化酶（ACE）基因插入／缺失（I／D）多态性与脑卒中的关系。方法 用聚合酶链反应（PCR）方法观察比较131名脑卒中患者及与其年龄相匹配的健康人50名的ACE基因I／D多态性。在实验中插入特异引物进行二次PCR扩增，以避免纯合子DD基因型的误判。结果 健康组对照、脑梗死组和脑出血组的基因型分布有差别（X^2=13．87，P=0．008），脑梗死组和脑出血组的DD基因型频率高于健康对照组的相应频率（X^2=9．21，P=0．002；X^2=8．76，P=0．003）。健康对照组、脑梗死组和脑出血组的D等位基因频率有差别（X^2=14．23，P=0．005），脑梗死组和脑出血组的D等位基因频率高于健康对照组的相应频率（X^2=11．17，P=0．00l；X^2=10．87，P=0．001）。结论 ACE基因具有I／D多态性，脑卒中与DD基因型和D等位基因有一定相关性，是可能引发脑卒中的危险遗传因素。     

The current status and future applications of gene therapy and immunogene therapy for malignant lymphoma

The present therapy for malignant lymphoma including stem cell transplantation, has been greatly developed. However, treatments still remain ineffective for many patients. Gene therapy is providing new strategies for the treatments of malignant lymphoma. There are three major approaches; 1) killing the tumor cell itself by introducing anti-sense genes against oncogene, tumor suppressor genes or drug-sensitive genes. 2) modifying the immune response by introducing genes that will trigger anti-tumor response or tumor specific genes to antigen presenting cell. 3) decreasing the sensitivity of hemopoietic cells by introducing drug resistance genes. We describe here the current and future applications of gene therapy for malignant lymphoma.     

The status of gene therapy for brain tumors

The advent of gene therapy in the early 1990's raised expectations for brain tumor therapies; however, whereas clinical trials in patients with malignant gliomas provided evidence of safety, therapeutic benefit was not convincing. These early forays resembled the historical introductions of other therapies that seemed promising, only to fail in human trials. Nevertheless, re-study in the laboratory and retesting in iterative laboratory-clinic processes enabled therapies with strong biological rationales to ultimately show evidence of success in humans and become accepted. Examples, such as organ transplantation, monoclonal antibody therapy and antiangiogenic therapy, provide solace that a strategy's initial lack of success in humans provides an opportunity for its further refinement in the laboratory and development of solutions that will translate into patient success stories. The authors herein summarize results from clinical trials of gene therapy for malignant gliomas, and discuss the influence of these results on present thought in preclinical research.     

基因治疗有效性和安全性分析

生物体的性状是由核苷酸序列构成的基因决定的。如果核苷酸序列发生了改变,就会导致生物体性状的改变。人类某些疾病的产生就是因为基因核苷酸序列的改变而引起的,校正被改变了的核苷酸序列-基因治疗就成了治疗这些疾病的首选方法。所谓基因治疗是将外源基因即正常的或野生型基因导入目的细胞,纠正和补偿致病基因产生的缺陷从而达到治疗疾病的目的。     

The application of gene therapy in autoimmune diseases

The application of gene therapy in autoimmune disease represents a novel use of this technology. The goal of gene therapy in the treatment of autoimmune disease is to restore 'immune homeostasis' by countering the pro-inflammatory effects of the CD4+ T cells in the lesions of autoimmunity. This can be accomplished by adoptive therapy with transduced T cells which can specifically home to the site of inflammation and secrete 'regulatory' protein(s) to ameliorate the inflammation or by direct targeting of the retroviral vector to activated T cells in the sites of inflammation. Transduction of autoantigen recognizing CD4+ T cells, to secrete anti-inflammatory products, may become the 'magic bullet' to combat the ravages of autoimmune inflammation and tissue destruction. Gene Therapy (2000) 7, 9-13.     

The prospect of gene therapy for lipid disorders

The refractory hyperlipoproteinemia that is associated with atherosclerotic vascular disease is a good candidate for somatic gene therapy. The molecular etiology and pathophysiology of these diseases are mostly well understood, the animal models for these diseases have been extensively developed, and the preclinical proof-of-principle gene transfer studies have already been performed. The clinical gene therapy trials performed in the last decade raised the issue of the necessity for the development of refined vectors that can stand for clinical usage. Recent progress in basic researches implies the feasibleness of the development of vectors that provide long-term and highly-efficient gene expression, which would potentially lead to the beginning of a new era in the field of gene therapy for lipid disorders.     

The use of molecular imaging of gene expression by radiotracers in gene therapy

Introduction: Progress with gene-based therapies has been hampered by difficulties in monitoring the biodistribution and kinetics of vector-mediated gene expression. Recent developments in non-invasive imaging have allowed researchers and clinicians to assess the location, magnitude and persistence of gene expression in animals and humans. Such advances should eventually lead to improvement in the efficacy and safety of current clinical protocols for future treatments.

Areas covered: The molecular imaging techniques for monitoring gene therapy in the living subject, with a specific highlight on the key reporter gene approaches that have been developed and validated in preclinical models using the latest imaging modalities. The applications of molecular imaging to biotherapy, with a particular emphasis on monitoring of gene and vector biodistribution and on image-guided radiotherapy.

Expert opinion: Among the reporter gene/probe combinations that have been described so far, one stands out, in our view, as the most versatile and easy to implement: the Na/I symporter. This strategy, exploiting more than 50 years of experience in the treatment of differentiated thyroid carcinomas, has been validated in different types of experimental cancers and with different types of oncolytic viruses and is likely to become a key tool in the implementation of human gene therapy.     

The use of molecular imaging of gene expression by radiotracers in gene therapy

INTRODUCTION: Progress with gene-based therapies has been hampered by difficulties in monitoring the biodistribution and kinetics of vector-mediated gene expression. Recent developments in non-invasive imaging have allowed researchers and clinicians to assess the location, magnitude and persistence of gene expression in animals and humans. Such advances should eventually lead to improvement in the efficacy and safety of current clinical protocols for future treatments. AREAS COVERED: The molecular imaging techniques for monitoring gene therapy in the living subject, with a specific highlight on the key reporter gene approaches that have been developed and validated in preclinical models using the latest imaging modalities. The applications of molecular imaging to biotherapy, with a particular emphasis on monitoring of gene and vector biodistribution and on image-guided radiotherapy. EXPERT OPINION: Among the reporter gene/probe combinations that have been described so far, one stands out, in our view, as the most versatile and easy to implement: the Na/I symporter. This strategy, exploiting more than 50 years of experience in the treatment of differentiated thyroid carcinomas, has been validated in different types of experimental cancers and with different types of oncolytic viruses and is likely to become a key tool in the implementation of human gene therapy.