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

2001 ◽  
Vol 7 (2) ◽  
pp. 79-94 ◽  
Author(s):  
SHARON C. FRANCIS ◽  
MOHAN K. RAIZADA ◽  
ABEEL A. MANGI ◽  
LUIS G. MELO ◽  
VICTOR J. DZAU ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Animal Models ◽  
Neointimal Hyperplasia ◽  
Experimental Studies ◽  
Current Status ◽  
No Production ◽  
Genetic Targeting

This article is based on an Experimental Biology symposium held in April 2001 and presents the current status of gene therapy for cardiovascular diseases in experimental studies and clinical trials. Evidence for the use of gene therapy to limit neointimal hyperplasia and confer myocardial protection was presented, and it was found that augmenting local nitric oxide (NO) production using gene transfer (GT) of NO synthase or interruption of cell cycle progression through a genetic transfer of cell cycle regulatory genes limited vascular smooth muscle hyperplasia in animal models and infra-inguinal bypass patients. The results of application of vascular endothelial growth factor (VEGF) GT strategies for therapeutic angiogenesis in critical limb and myocardial ischemia in pilot clinical trials was reviewed. In addition, experimental evidence was presented that genetic manipulation of peptide systems (i.e., the renin-angiotensin II system and the kallikrein-kinin system) was effective in the treatment of systemic cardiovascular diseases such as hypertension, heart failure, and renal failure. Although, as of yet, there are no well controlled human trials proving the clinical benefits of gene therapy for cardiovascular diseases, the data presented here in animal models and in human subjects show that genetic targeting is a promising and encouraging modality, not only for the treatment and long-term control of cardiovascular diseases, but for their prevention as well.

Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 112-125 ◽  
Author(s):  
Kelly Ceyzériat ◽  
Thomas Zilli ◽  
Philippe Millet ◽  
Giovanni B. Frisoni ◽  
Valentina Garibotto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Phase Iii ◽  
Current Status ◽  
Central Feature ◽  
Phase Iii Trial ◽  
The Past ◽  
Positive Results

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

scholarly journals Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

2020 ◽  
pp. bjophthalmol-2020-316195 ◽  
Author(s):  
Thales Antonio Cabral de Guimaraes ◽  
Michalis Georgiou ◽  
James W B Bainbridge ◽  
Michel Michaelides
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Current Status ◽  
Routes Of Administration ◽  
Age Related ◽  
Potential Safety ◽  
Early Phase Clinical Trials ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections—even lifelong—and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.

scholarly journals Current Status and Developments in Gene Therapy for Thalassemia and Sickle Cell Disease

2014 ◽  
Vol 4 (3) ◽  
pp. 75-80
Author(s):  
Evangelia Yannaki ◽  
Garyfalia Karponi
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Autologous Transplantation ◽  
Current Status ◽  
Successful Implementation ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Monogenic Diseases

β-thalassemias and sickle cell anemia (SCA) are the most common monogenic diseases worldwide for which curative treatments remain a desired goal. Allogeneic hematopoietic stem cell transplantation (allo-HCT), - the only curative treatment currently available for hemoglobinopaties-, has a narrow application window whereas it incurs several immunological risks. Gene therapy (GT), that is the autologous transplantation of genetically modified hematopoietic stem cells (CD34+), represents a promising new therapeutic strategy which is anticipated to reestablish effective hemoglobin production and render patients transfusion- and drug- independent without the immunological complications that normally accompany allo-HCT. Prior to the application of GT for hemoglobinopathies in the clinic, many years of extensive preclinical research were spent for the optimization of the gene transfer tools and conditions. To date, three GT clinical trials for β-thalassemia and sickle cell disease (SCD) have been conducted or are in progress and 3 cases of transfusion independence in thalassemic β0/βΕ patients have been reported. In the present review, the prerequisites for successful implementation of GT, the tough pathway of GT for hemoglobinopathies towards the clinic and the knowledge gained from the first clinical trials as well as the remaining questions and challenges, will be discussed. Overall, after decades of research including achievements but pitfalls as well, the path to GT of human patients with hemoglobinopathies is currently open and highly promising...

scholarly journals Gene Therapy for Cardiovascular Disease

2003 ◽  
Vol 2003 (2) ◽  
pp. 138-148 ◽  
Author(s):  
Kate L. Dishart ◽  
Lorraine M. Work ◽  
Laura Denby ◽  
Andrew H. Baker
Keyword(s):  
Cardiovascular Disease ◽  
Gene Therapy ◽  
Drug Therapy ◽  
Cardiovascular Diseases ◽  
Gene Transfer ◽  
Animal Models ◽  
Pharmacological Treatments ◽  
Therapy Strategies ◽  
Vascular Gene Transfer

The last decade has seen substantial advances in the development of gene therapy strategies and vector technology for the treatment of a diverse number of diseases, with a view to translating the successes observed in animal models into the clinic. Perhaps the overwhelming drive for the increase in vascular gene transfer studies is the current lack of successful long-term pharmacological treatments for complex cardiovascular diseases. The increase in cardiovascular disease to epidemic proportions has also led many to conclude that drug therapy may have reached a plateau in its efficacy and that gene therapy may represent a realistic solution to a long-term problem. Here, we discuss gene delivery approaches and target diseases.

scholarly journals Cancer Gene Therapy

2005 ◽  
Vol 4 (4) ◽  
pp. 315-330 ◽  
Author(s):  
Masato Yamamoto ◽  
David T. Curiel
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Continuous Infusion ◽  
Cancer Gene Therapy ◽  
Therapeutic Modality ◽  
Current Status ◽  
Cancer Gene ◽  
Gastrointestinal Cancers ◽  
Delivery Method ◽  
Promising Strategy

The prognosis of patients with some kinds of cancers whose patients are often found unresectable upon diagnosis is still dismal. In these fields, development of a new therapeutic modality is needed and gene therapy represents one promising strategy. So far, numerous cancer gene therapy clinical trials based on these principles have been carried out and have shown the safety of such modalities, but have fallen short of the initial expectations to cure cancers. In this review, we would like to make a problem-oriented discussion of current status of cancer gene therapy research by using mainly gastrointestinal cancers as an example. In order to overcome obstacles for full realization of cancer gene therapy, numerous researches have been conducted by many researchers. Various cancer-selective and non-selective genes, as well as lytic viruses themselves have been employed for gene therapy. In the context of gene delivery method, different kinds of viral and non-viral strategies have been utilized. In addition, surrogate assays, such as soluble markers and imaging, have been developed for safer and more informative clinical trials. Many experiments and clinical trials to date have figured out current obstacles for the realization of an effective cancer gene therapy modality. Tireless efforts to overcome such hurdles and continuous infusion of novel concepts into this field should lead to break through technologies and the cure of the patients.

scholarly journals Experimental models of sepsis and septic shock: an overview

2004 ◽  
Vol 19 (2) ◽  
pp. 82-88 ◽  
Author(s):  
Alejandra G. Garrido ◽  
Luiz Francisco Poli de Figueiredo ◽  
Maurício Rocha e Silva
Keyword(s):  
Septic Shock ◽  
Clinical Trials ◽  
Animal Models ◽  
Cecal Ligation ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Contributing Factors ◽  
Human Sepsis ◽  
Sepsis And Septic Shock

Sepsis remains a major cause of morbidity and mortality in surgical patients and trauma victims, mainly due to sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have fails to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies, and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the benefits and limitations of various animal models of sepsis are discussed to clarify the extend to which findings are relevant to human sepsis, particularly with respect to the subsequent design and execution of clinical trials. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models, using different animal species including rats, mice, rabbits, dogs, pigs, sheep and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock, because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be duplicated by other methods. New therapeutic agents should be studies in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient.

scholarly journals Health Benefits and Molecular Mechanisms of Resveratrol: A Narrative Review

Foods ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 340 ◽  
Author(s):  
Xiao Meng ◽  
Jing Zhou ◽  
Cai-Ning Zhao ◽  
Ren-You Gan ◽  
Hua-Bin Li
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Chronic Diseases ◽  
Liver Diseases ◽  
Molecular Mechanisms ◽  
Health Benefits ◽  
Experimental Studies ◽  
Bioactive Compound ◽  
Protective Effects ◽  
Epidemiological Surveys

Resveratrol is a bioactive compound in many foods. Since its anticancer activity was reported in 1997, its health benefits have been intensively investigated. Resveratrol has antioxidant, anti-inflammatory, immunomodulatory, glucose and lipid regulatory, neuroprotective, and cardiovascular protective effects, therefore, can protect against diverse chronic diseases, such as cardiovascular diseases (CVDs), cancer, liver diseases, obesity, diabetes, Alzheimer’s disease, and Parkinson’s disease. This review summarizes the main findings of resveratrol-related health benefits in recent epidemiological surveys, experimental studies, and clinical trials, highlighting its related molecular mechanisms. Resveratrol, therefore, has been regarded as a potent candidate for the development of nutraceuticals and pharmaceuticals to prevent and treat certain chronic diseases.

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