Gene therapy legislation in The Netherlands

Several regulatory organisations are involved in the assessment of clinical gene therapy trials involving genetically modified organisms (GMOs) in The Netherlands. Medical, ethical and scientific aspects are, for instance, evaluated by the Central Committee on Research Involving Human Subjects (CCMO). The Ministry of Housing, Spatial Planning and the Environment (VROM) is the competent authority for the environmental risk assessment according to the deliberate release Directive 2001/18/EC. A Gene Therapy Office has been established in order to streamline the different national review processes and to enable the official procedures to be completed as quickly as possible. Although the Gene Therapy Office improved the application process at the national level, there is a difference of opinion between the EU member states with respect to the EU Directive according to which gene therapy trials are assessed, that urges for harmonisation. This review summarises the gene therapy legislation in The Netherlands and in particular The Netherlands rationale to follow Directive 2001/18/EC for the environmental risk assessment.     

Gene therapy clinical trials worldwide to 2017: An update

To date, almost 2600 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our November 2017 update, we have entries on 2597 trials undertaken in 38 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and the genes that have been transferred. Details of the analyses presented, and our searchable database are available via The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical . We also provide an overview of the progress being made in gene therapy clinical trials around the world, and discuss key trends since the previous review, namely the use of chimeric antigen receptor T cells for the treatment of cancer and advancements in genome editing technologies, which have the potential to transform the field moving forward.     

Gene therapy moves forward - The Second International Meeting on Gene and Cell Therapies of Arthritis and Related Disorders, 17-18 May 2001, Montpellier, France

The field of gene therapy for bone and joint disorders has grown considerably over the last two and a half years. Investigators have shown that ex vivo or in vivo gene transfer is highly effective in blocking arthritis or facilitating repair of damaged cartilage or bone. The feasibility of applying gene therapy for the treatment of arthritis in humans has also been demonstrated. Thus, gene therapy appears poised to make significant contributions to the clinical treatment of joint and bone diseases in the near future.     

Gene therapy for achromatopsia

The present review summarizes the current status of achromatopsia (ACHM) gene therapy‐related research activities and provides an outlook for their clinical application. ACHM is an inherited eye disease characterized by a congenital absence of cone photoreceptor function. As a consequence, ACHM is associated with strongly impaired daylight vision, photophobia, nystagmus and a lack of color discrimination. Currently, six genes have been linked to ACHM. Up to 80% of the patients carry mutations in the genes CNGA3 and CNGB3 encoding the two subunits of the cone cyclic nucleotide‐gated channel. Various animal models of the disease have been established and their characterization has helped to increase our understanding of the pathophysiology associated with ACHM. With the advent of adeno‐associated virus vectors as valuable gene delivery tools for retinal photoreceptors, a number of promising gene supplementation therapy programs have been initiated. In recent years, huge progress has been made towards bringing a curative treatment for ACHM into clinics. The first clinical trials are ongoing or will be launched soon and are expected to contribute important data on the safety and efficacy of ACHM gene supplementation therapy.     

Gene therapy clinical trials worldwide to 2012 – an update

To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical . We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future. Copyright © 2013 John Wiley & Sons, Ltd.     

Gene therapy in cancer

Gene therapy, recently frequently investigated, is an alternative treatment method that introduces therapeutic genes into a cancer cell or tissue to cause cell death or slow down the growth of the cancer. This treatment has various strategies such as therapeutic gene activation or silencing of unwanted or defective genes; therefore a wide variety of genes and viral or nonviral vectors are being used in studies. Gene therapy strategies in cancer can be classified as inhibition of oncogene activation, activation of tumor suppressor gene, immunotherapy, suicide gene therapy and antiangiogenic gene therapy. In this review, we explain gene therapy, gene therapy strategies in cancer, approved gene medicines for cancer treatment and future of gene therapy in cancer. Today gene therapy has not yet reached the level of replacing conventional therapies. However, with a better understanding of the mechanism of cancer to determine the right treatment and target, in the future gene therapy, used as monotherapy or in combination with another existing treatment options, is likely to be used as a new medical procedure that will make cancer a controllable disease.     

The ecology of The Netherlands wetlands: characteristics,threats, prospects and perspectives for ecological research

Wetlands are among the worlds' most important, but also most threatened, environmental resources. Wetland losses have been in progress particularly from the industrial revolution onwards, because wetland functions could not successfully compete for space with other land uses. Wetlands became recently foci of conservation efforts because of the increased awareness of their importance in water management and wildlife conservation, and because of the diversity of their habitats. The Netherlands are relatively rich in wetlands: 16% of its' territory is regarded as internationally important wetland and 7% has been registered as such. The major Dutch wetland types are: coastal ecosystems, large riverine systems, base-rich freshwater systems, and nutrient-poor freshwater systems. Most threats to the Dutch wetlands are of man-made origin. They comprise: (1) Changes in hydrology leading to changed discharges, currents and desiccation; (2) Acidification; (3) Eutrophication; and (4) Toxification. Long-term threats are largely climate-change related, and concern temperature rise and the UV-B increase in irradiation. General conservation goals also apply to wetlands but Ramsar-registered wetlands have a special status. Conservation of the Dutch wetlands is difficult, because of the high population density of the country and its inherent threats. However, ecological targets and standards are increasingly set in national Policy Plans and international agreements. Rehabilitation and creation of wetlands is presently widely advocated, and sometimes realised. For ecological research, the sustainability of wetlands should get top priority. Such a research programme would focus on understanding the underlying ecological processes in natural and man-dominated wetland systems to prescribe conservation, rehabilitation and management strategies that would enhance the sustainability of these systems. Within this framework special attention should be directed to studies (1) At the ecosystem level of ecosystem parameters, of which natural oscillations and trends in time, and on which the impact of disturbances are quantified. Particularly these studies, in which often simulation models are used as tools for interpretation, can provide the basis for extrapolations in space and time; (2) On adaptation capacity and mechanisms of (groups of) species to extreme environmental conditions; (3) On (mutual) relationships between plants, animals and microorganisms (e.g. competition, grazing and mineralization); (4) On dispersion between small wetlands. For the contemporary quantitative assessment of the long-term effects of climate changes, the effects of temperature rise and increase in UV-B irradiation on individual species, communities and ecosystems should also be studied.     

History of diatom research in The Netherlands and Flanders

The history of diatom research in The Netherlands and Flanders is summarized in this report. A. van Leeuwenhoek observed diatoms as early as 1702. The first inventories were made in The Netherlands by R. B. van den Bosch (1846) and in Flanders by J.-J. Kickx (1867). Diatoms were already used in geological research in the second half of the nineteenth century. The Synopsis by H. van Heurck (1880–1885) enabled many twentieth century workers to do applied research for geological and ecological purposes.     

Denitrification and dinitrogen fixation in two quaking fens in the Vechtplassen area,The Netherlands

This paper reports laboratory experiments on dinitrogen fixation and denitrification for two small quaking fens (discharge fen and recharge fen) using the acetylene reduction assay and the acetylene inhibition technique, respectively.Nitrogenase activity was detected in peat muck and associated with Alnus glutinosa saplings throughout the study period (May–October 1987), whereas no activity was observed with Sphagnum species. The annual amount of dinitrogen fixed was estimated at 2.1 and 12.7 kg N/ha/y for the recharge fen and the discharge fen, respectively.Denitrification at ambient nitrate levels (0.1 ppm NO₃) was absent in the discharge fen and very low in the recharge fen (0.1 g N/g/d, or 0.3 kg N/ha/y). In nitrate-amended soil samples denitrification rates were 2 to 3 orders of magnitude higher. It is argued that in situ denitrification rates in the fens studied will depend almost entirely on the nitrate supply by precipitation. Denitrification rates associated with precipitation are estimated at 1.1 kg N/ha/y for both fens.     

电穿孔基因导入技术在临床前与临床试验中的应用

电穿孔基因作为非病毒递送手段之一,可安全、有效地将外源核酸导入靶组织或器官。近年来用电穿孔法进行基因治疗的报道不断增多,优势日趋显著。本文重点阐述了电穿孔在基因治疗中的优势、影响因素及在临床前和临床试验中应用。     

Gene therapy: progress and predictions

The first clinical gene delivery, which involved insertion of a marker gene into lymphocytes from cancer patients, was published 25 years ago. In this review, we describe progress since then in gene therapy. Patients with some inherited single-gene defects can now be treated with their own bone marrow stem cells that have been engineered with a viral vector carrying the missing gene. Patients with inherited retinopathies and haemophilia B can also be treated by local or systemic injection of viral vectors. There are also a number of promising gene therapy approaches for cancer and infectious disease. We predict that the next 25 years will see improvements in safety, efficacy and manufacture of gene delivery vectors and introduction of gene-editing technologies to the clinic. Gene delivery may also prove a cost-effective method for the delivery of biological medicines.     

Gene delivery methods in cardiac gene therapy

Gene therapy for the treatment of heart failure is emerging as a multidisciplinary field demonstrating advances with respect to identifying key signaling pathways, modernized vector creation and delivery technologies. Although these discoveries offer significant progress, selecting optimal methods for the vector delivery remains a key component for efficient cardiac gene therapy to validate the targets in rodent models and to test clinically relevant ones in pre-clinical models. Although the goals of higher transduction efficiency and cardiac specificity can be achieved with several delivery methods, the invasiveness and patient safety remain unclear for clinical application. In this review, we discuss various features of the currently available vector delivery methods for cardiac gene therapy.     

The distribution of Chironomid larvae in relation to Chloride concentration in a brackish water region of the Netherlands

Drainage ditches are a familiar and common habitat in the Netherlands. Until recently however they have been the focus of few ecological studies. Extensive studies on Walcheren, a brackish water region of The Netherlands, have shown that chironomid larvae form a major component of the animal communities in the mud. The spatial distribution of some of these species can be correlated with the chloride concentration of the water. Biometric data are included for the speciesChironomus salinarius, C. halophilus andC. plumosus. Communication nr. 151 of the Delta Institute for Hydrobiological Research     

Perinatal mortality in Utrecht, The Netherlands, 1880–1940

The secular trend of perinatal mortality in Utrecht between 1880 and 1940 and its causes are examined in this study, based on patient records of two maternity clinics, those of the city's academic hospital, and of its outpatient clinic. The sample includes 17,111 deliveries. Over the period the proportion of births in the city occurring in the two institutions rose from 3 to 90%. The perinatal mortality rate in the hospital declined and then rose slightly at the end of the 19th century, but remained constant, even if cyclical, thereafter in both the hospital and the outpatient clinic. Rates differed substantially between the two maternity services. Logistic regression analysis reveals a cluster of factors related to perinatal death. Low birth weight had a powerful association with perinatal mortality in both samples. Most of the other factors associated with perinatal mortality were related to the health of the patients, to obstetric problems related to deliveries, and to infant sex and maternal age. Relationships between perinatal mortality and other measures of human welfare in The Netherlands are explored.     

The choice between desiccation of wetlands or the spread of Rhine water over The Netherlands

The dry summer of 1976 triggered a wholesale installation of sprinkler systems for agriculture. This dry summer also revealed areas in The Netherlands most susceptible to drought, namely sandy regions and the coastal fringe. This resulted in distribution of Rhine water to new areas, and in quantities hitherto unknown. The Second National Water Management Plan (1982) consequently focussed on enlarging the capacity of water distribution works. This distribution has led to a multitude of ecological effects, such as changes in salinity and nutrient concentration, as well as the spreading of contaminants. Consequently, the Third National Water Management Plan (1990) includes fewer distribution works because of the adverse environmental effects and the reduced feasibility due to increasing costs and decreasing agricultural benefits.A climatic change as predicted may result in climatic conditions in The Netherlands resembling those of France or the Mediterranean, implying drier summers and more precipitation in winter. An increased frequency of dry summers will no doubt revive water distribution plans now shelved and may even bring new ones to the drawing board. An increase in Rhine water distribution will have serious consequences for many aquatic and terrestrial ecosystems, as will a lowering of the groundwater table. In this paper we will discuss the dilemma of choosing between allowing increased desiccation of wetlands as the climate becomes drier or increasing the distribution of Rhinewater and the potential ecological effects of these choices. Alternative strategies to water management also are discussed.This article is largely based on Duel et al. 1989.     

Changing landscape and grazing: macroremains from the terp Peins-east, province of Friesland, the Netherlands

This article seeks to contribute some new insights to the discussion about the colonisation of the North-Netherlands coastal area in the Iron Age. The aim of the study presented here was to investigate whether archaeobotanical research can demonstrate the absence or presence of grazing and the changes in vegetation that follow the development of the salt marsh and that may be related to activities connected with human occupation. The material studied was sampled in the terp of Peins in the Dutch province of Friesland during the 1999 excavation. The beginnings of this terp can be dated in the first century A.D., although a small dike and two parallel ditches preceded it. The macroremains from these ditches proved useful in describing the changes in the salt marsh vegetation. It was shown that the salt marsh was not used for grazing cattle prior to habitation. Grazing only started at the time the first terp podium was raised.