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1.
J Gene Med ; 26(8): e3721, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39114903

RESUMEN

To date, 3,900 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 March 2023 update, we have entries on 3,900 trials undertaken in 46 countries. We have analyzed 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 on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at https://a873679.fmphost.com/fmi/webd/GTCT. We also provide an overview of the progress being made around the world, and discuss key trends since the previous review, namely the unprecedented increase in gene therapy clinical trial activity, including the implementation of genome editing technology with the potential to transform the field moving forward.


Asunto(s)
Ensayos Clínicos como Asunto , Terapia Genética , Humanos , Terapia Genética/métodos , Terapia Genética/tendencias , Edición Génica/métodos , Vectores Genéticos
2.
Platelets ; 34(1): 2159018, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36632714

RESUMEN

Platelets are transfused to patients to prevent bleeding. Since both preparation and storage can impact the hemostatic functions of platelets, we studied platelet concentrates (PCs) with different initial composition in regard to platelet fragmentation and its impact on storage-induced changes in activation potential. Ten whole blood derived PCs were assessed over 7 storage days. Using flow cytometry, platelet (CD41+) subpopulations were characterized for activation potential using activation markers (PAC-1, P-selectin, and LAMP-1), phosphatidylserine (Annexin V), and mitochondrial integrity (DiIC1(5)). Aggregation response, coagulation, and soluble activation markers (cytokines and sGPVI) were also measured. Of the CD41+ events, the PCs contained a median of 82% normal-sized platelets, 10% small platelets, and 8% fragments. The small platelets exhibited procoagulant hallmarks (increased P-selectin and Annexin V and reduced DiIC1(5)). Normal-sized platelets responded to activation, whereas activation potential was decreased for small and abolished for fragments. Five PCs contained a high proportion of small platelets and fragments (median of 28% of CD41+ events), which was significantly higher than the other five PCs (median of 9%). A high proportion of small platelets and fragments was associated with procoagulant hallmarks and decreased activation potential, but, although diminished, they still retained some activation potential throughout 7 days storage.


What is the context?● Platelets are necessary to prevent and stop bleeding.● Conditions associated with a low platelet count in the circulation, such as during chemotherapy treatment for hematologic cancer, can result in life-threatening bleeding. To prevent this, platelets from blood donors are transfused to these patients.● The collection and preparation of platelet concentrates and subsequent storage before transfusion can affect the ability of the platelets to prevent bleeding.● In this study, we investigated platelet concentrates prepared from whole blood and how their activation capacity was affected by the preparation and storage period.What is new?● We found that the platelet concentrates contained mainly low activated platelets of normal size, but also smaller platelets and platelet fragments.● Unlike normal-sized platelets, small platelets and fragments exhibited hallmarks that are characteristic of pre-activation.● Some platelet concentrates contained a relatively high proportion of small platelets and fragments already directly following preparation.● Investigating several platelet activation markers, we found that platelet concentrates containing a high proportion of small platelets and platelet fragments showed lower activation capacity throughout the storage period.What is the impact?● We show that some platelet concentrates show lower activation capacity and might contain a substantial fraction of platelets with characteristics that might potentially trigger spontaneous blood coagulation. The variation between different concentrations is high, even though the preparation procedure is the same.● If these differences will affect the efficacy of platelet transfusion is an important area for future studies.


Asunto(s)
Plaquetas , Activación Plaquetaria , Humanos , Anexina A5/metabolismo , Coagulación Sanguínea , Plaquetas/metabolismo , Conservación de la Sangre , Selectina-P/metabolismo
3.
J Gene Med ; 20(5): e3015, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29575374

RESUMEN

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.


Asunto(s)
Ensayos Clínicos como Asunto/métodos , Terapia Genética/métodos , Salud Global/estadística & datos numéricos , Neoplasias/terapia , Ensayos Clínicos como Asunto/estadística & datos numéricos , Terapia Genética/tendencias , Salud Global/tendencias , Humanos , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/tendencias , Neoplasias/genética , Evaluación de Resultado en la Atención de Salud
4.
J Gene Med ; 15(2): 65-77, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23355455

RESUMEN

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.


Asunto(s)
Ensayos Clínicos como Asunto , Terapia Genética/métodos , Animales , Enfermedades Cardiovasculares/terapia , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Terapia Genética/tendencias , Vectores Genéticos , Humanos , Neoplasias/terapia , Virus/genética
5.
J Vis Exp ; (70): e4414, 2012 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-23242463

RESUMEN

Blood centers are faced with many challenges including maximizing production yield from the blood product donations they receive as well as ensuring the highest possible level of safety for transfusion patients, including protection from transfusion transmitted diseases. This must be accomplished in a fiscally responsible manner which minimizes operating expenses including consumables, equipment, waste, and personnel costs, among others. Several methods are available to produce platelet concentrates for transfusion. One of the most common is the buffy coat method in which a single therapeutic platelet unit (≥ 2.0 x10(11) platelets per unit or per local regulations) is prepared by pooling the buffy coat layer from up to six whole blood donations. A procedure for producing "double dose" whole blood derived platelets has only recently been developed. Presented here is a novel method for preparing double dose whole blood derived platelet concentrates from pools of 7 buffy coats and subsequently treating the double dose units with the INTERCEPT Blood System for pathogen inactivation. INTERCEPT was developed to inactivate viruses, bacteria, parasites, and contaminating donor white cells which may be present in donated blood. Pairing INTERCEPT with the double dose buffy coat method by utilizing the INTERCEPT Processing Set with Dual Storage Containers (the "DS set"), allows blood centers to treat each of their double dose units in a single pathogen inactivation processing set, thereby maximizing patient safety while minimizing costs. The double dose buffy coat method requires fewer buffy coats and reduces the use of consumables by up to 50% (e.g. pooling sets, filter sets, platelet additive solution, and sterile connection wafers) compared to preparation and treatment of single dose buffy coat platelet units. Other cost savings include less waste, less equipment maintenance, lower power requirements, reduced personnel time, and lower collection cost compared to the apheresis technique.


Asunto(s)
Eliminación de Componentes Sanguíneos/métodos , Plaquetas/citología , Plaquetas/microbiología , Humanos , Transfusión de Plaquetas/métodos
6.
Int Immunopharmacol ; 10(11): 1420-7, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20816993

RESUMEN

It is well established that exposure of mice to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) induces hepatomegaly and, concurrently, immunotoxicity. However, the effects of these perfluorochemicals on the histology and immune status of the liver have not been yet investigated and we have examined these issues here. Dietary treatment of male C57BL/6 mice with 0.002% (w/w) PFOA or 0.005% (w/w) PFOS for 10 days resulted in significant reductions in serum levels of cholesterol and triglycerides, a moderate increase in the serum activity of alkaline phosphatase (ALP) and hepatomegaly, without affecting other immune organs. This hepatomegaly was associated with marked hypertrophy of the centrilobular hepatocytes, with elevated numbers of cytoplasmic acidophilic granules and occasional mitosis. Furthermore, dietary exposure to PFOA or PFOS altered the hepatic immune status: whereas exposure to PFOA enhanced the numbers of total, as well as of phenotypically distinct subpopulations of intrahepatic immune cells (IHIC), and in particular the presumptive erythrocyte progenitor cells, treatment with PFOS enhanced only the numbers of hepatic cells that appear immunophenotypically to be erythrocyte progenitors, without affecting other types of IHIC. In addition, exposure to these compounds attenuated hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Furthermore, the exposed animals exhibited a significant increase in hepatic levels of erythropoietin, a hormone required for erythropoiesis. Thus, in mice, PFOA- and PFOS-induced hepatomegaly is associated with significant alterations in hepatic histophysiology and immune status, as well as induction of hepatic erythropoiesis.


Asunto(s)
Ácidos Alcanesulfónicos/toxicidad , Caprilatos/toxicidad , Contaminantes Ambientales/toxicidad , Fluorocarburos/toxicidad , Hepatomegalia/inducido químicamente , Hígado/efectos de los fármacos , Fosfatasa Alcalina/sangre , Ácidos Alcanesulfónicos/administración & dosificación , Animales , Caprilatos/administración & dosificación , Colesterol/sangre , Dieta/efectos adversos , Contaminantes Ambientales/administración & dosificación , Eritropoyetina/análisis , Fluorocarburos/administración & dosificación , Hepatomegalia/inmunología , Interferón gamma/análisis , Interleucina-4/análisis , Hígado/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitosis/efectos de los fármacos , Mitosis/inmunología , Triglicéridos/sangre , Factor de Necrosis Tumoral alfa/análisis
7.
Blood ; 112(2): 277-86, 2008 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-18319398

RESUMEN

The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.


Asunto(s)
Inmunodeficiencia Variable Común/clasificación , Edad de Inicio , Autoinmunidad , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/mortalidad , Inmunodeficiencia Variable Común/patología , Humanos , Isotipos de Inmunoglobulinas/sangre , Infiltración Leucémica , Fenotipo , Pronóstico , Sistema de Registros
8.
J Gene Med ; 9(10): 833-42, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17721874

RESUMEN

To date, over 1340 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. In 1997 we set up a database to bring together global information on gene therapy clinical trials as comprehensively as possible. The data are compiled and regularly updated from official agency sources, published literature, conference presentations and posters and from information kindly provided by investigators or trial sponsors themselves. This review updates our descriptive overview of the data in 2004 1, presenting our analysis of the clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of July 30 2007, we have stored entries on 1309 trials in 28 countries. We have analyzed 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 interactive, searchable database can be found on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical.


Asunto(s)
Terapia Genética/métodos , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/terapia , Ensayos Clínicos como Asunto/estadística & datos numéricos , Ensayos Clínicos como Asunto/tendencias , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Vectores Genéticos/uso terapéutico , Humanos , Neoplasias/genética , Neoplasias/terapia
9.
J Gene Med ; 6(6): 597-602, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15170730

RESUMEN

In 1989, Rosenberg et al. performed the first human gene therapy trial when they used a retrovirus to introduce the gene coding for resistance to neomycin into human tumor-infiltrating lymphocytes before infusing them into five patients with advanced melanoma. This study demonstrated the feasibility of using retroviral gene transduction in humans and set the stage for further studies. Since then, over 900 clinical trials have been completed, are ongoing or have been approved worldwide. These trials have been designed to establish feasibility and safety, to demonstrate the reality of expression of therapeutic protein(s) in vivo by the genes transferred and, in some cases, to show therapeutic benefit. There is no single source of information that presents an overview of all the clinical trials undertaken worldwide. In 1997 we set up a database to bring all the information on clinical trials together as comprehensively and as globally as possible. The data were compiled and are regularly updated from official agency sources, the published literature, presentations at conferences and from information kindly provided by investigators or trial sponsors themselves. As of January 31, 2004, we have identified 918 trials in 24 countries. The USA accounts for two-thirds of these trials. Cancer is by far the most common disease indication, followed by inherited monogenic diseases, and cardiovascular diseases. Viral vectors have been the most frequently used vehicles for transferring genes into human cells, with retroviruses and adenoviruses representing the vast majority. Plasmid (naked) DNA and other non-viral vectors have been used in one-quarter of the trials. Over 100 distinct genes have been transferred. This article aims to provide a descriptive overview of the clinical trials that, to the best of our knowledge, have been or are being performed worldwide. Details of the data presented, including an interactive, searchable database that currently holds information on 918 trials, can be found on The Journal of Gene Medicine clinical trials website 1.


Asunto(s)
Ensayos Clínicos como Asunto/estadística & datos numéricos , Terapia Genética/métodos , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/terapia , Ensayos Clínicos como Asunto/tendencias , Enzimas/genética , Genes Supresores de Tumor , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Vectores Genéticos/genética , Humanos , Inmunoterapia/métodos , Neoplasias/genética , Neoplasias/terapia , Profármacos
10.
Biol Blood Marrow Transplant ; 10(2): 128-34, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14750078

RESUMEN

The aim of this study was to identify significant prognostic factors by using unrelated genomically HLA-A, -B and -DRB1-identical donors. Such data could help to choose the best donor. We studied 136 consecutive patients with hematologic malignancies and a median age of 32 years (range, 0-55 years) who received hematopoietic stem cell transplantation. Bone marrow grafts were given to 83 and peripheral blood stem cells to 53 patients. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 30% and of chronic GVHD was 54%. At 5 years, the overall transplant-related mortality (TRM) was 34%, and patient survival was 50%. In Cox multivariate analysis, 32 potential risk factors were analyzed. Monoclonal antibody OKT-3 during conditioning was correlated with grade II to IV acute GVHD, chronic GVHD, and TRM. HLA-DP mismatch was associated with poor TRM and poor survival. Cytomegalovirus-seropositive patients with a seronegative donor had a decreased leukemia-free survival. Five-year TRM was 14% with no risk factor, 38% with 1 risk factor, and 87% with 2 risk factors. The 5-year survival was 72%, 48%, and 30% with 0, 1, and 2 risk factors, respectively. We concluded that unrelated hematopoietic stem cell transplantation may be improved if an optimal donor and immunosuppression are chosen.


Asunto(s)
Antígenos HLA/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Histocompatibilidad/genética , Donantes de Tejidos , Adolescente , Adulto , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/mortalidad , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/etiología , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante de Células Madre de Sangre Periférica/mortalidad , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia
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