scholarly journals Thrombospondin-1 CD47 Signalling: From Mechanisms to Medicine

2021 ◽  
Vol 22 (8) ◽  
pp. 4062
Author(s):  
Atharva Kale ◽  
Natasha M. Rogers ◽  
Kedar Ghimire
Keyword(s):  
Clinical Trials ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Phase 1 ◽  
Enzymatic Production ◽  
Animal Models Of Disease ◽  
Recent Advances ◽  
Thrombospondin 1 ◽  
Substantial Progress ◽  
Models Of Disease

Recent advances provide evidence that the cellular signalling pathway comprising the ligand-receptor duo of thrombospondin-1 (TSP1) and CD47 is involved in mediating a range of diseases affecting renal, vascular, and metabolic function, as well as cancer. In several instances, research has barely progressed past pre-clinical animal models of disease and early phase 1 clinical trials, while for cancers, anti-CD47 therapy has emerged from phase 2 clinical trials in humans as a crucial adjuvant therapeutic agent. This has important implications for interventions that seek to capitalize on targeting this pathway in diseases where TSP1 and/or CD47 play a role. Despite substantial progress made in our understanding of this pathway in malignant and cardiovascular disease, knowledge and translational gaps remain regarding the role of this pathway in kidney and metabolic diseases, limiting identification of putative drug targets and development of effective treatments. This review considers recent advances reported in the field of TSP1-CD47 signalling, focusing on several aspects including enzymatic production, receptor function, interacting partners, localization of signalling, matrix-cellular and cell-to-cell cross talk. The potential impact that these newly described mechanisms have on health, with a particular focus on renal and metabolic disease, is also discussed.

scholarly journals Taenia solium microRNAs: Potential Biomarkers and Drug Targets in Neurocysticercosis

2021 ◽  
Author(s):  
Matías Gastón Pérez
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Cell Growth ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Taenia Solium ◽  
Non Coding Rnas ◽  
Host Parasite ◽  
Potential Biomarkers

MicroRNAs (miRNAs) found in animals, plants, and some viruses belongs to the heterogeneous class of non-coding RNAs (ncRNAs), which posttranscriptional regulates gene expression. They are linked to various cellular activities such as cell growth, differentiation, development and apoptosis. Also, they have been involved in cancer, metabolic diseases, viral infections and clinical trials targeting miRNAs has shown promising results. This chapter provides an overview on Taenia solium and Taenia crassiceps miRNAs, their possible biological functions, their role in host–parasite communication and their potential role as biomarkers and drug targets.

scholarly journals The Application of Adeno-Associated Viral Vector Gene Therapy to the Treatment of Fragile X Syndrome

2019 ◽  
Vol 9 (2) ◽  
pp. 32 ◽  
Author(s):  
David Hampson ◽  
Alexander Hooper ◽  
Yosuke Niibori
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Fragile X Syndrome ◽  
Viral Vectors ◽  
Viral Vector ◽  
Fragile X ◽  
Animal Models Of Disease ◽  
Key Issues ◽  
Full Correction ◽  
Models Of Disease

Viral vector-mediated gene therapy has grown by leaps and bounds over the past several years. Although the reasons for this progress are varied, a deeper understanding of the basic biology of the viruses, the identification of new and improved versions of viral vectors, and simply the vast experience gained by extensive testing in both animal models of disease and in clinical trials, have been key factors. Several studies have investigated the efficacy of adeno-associated viral (AAV) vectors in the mouse model of fragile X syndrome where AAVs have been used to express fragile X mental retardation protein (FMRP), which is missing or highly reduced in the disorder. These studies have demonstrated a range of efficacies in different tests from full correction, to partial rescue, to no effect. Here we provide a backdrop of recent advances in AAV gene therapy as applied to central nervous system disorders, outline the salient features of the fragile X studies, and discuss several key issues for moving forward. Collectively, the findings to date from the mouse studies on fragile X syndrome, and data from clinical trials testing AAVs in other neurological conditions, indicate that AAV-mediated gene therapy could be a viable strategy for treating fragile X syndrome.

scholarly journals Improving preclinical studies through replications

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Natascha Ingrid Drude ◽  
Lorena Martinez Gamboa ◽  
Meggie Danziger ◽  
Ulrich Dirnagl ◽  
Ulf Toelch
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Large Scale ◽  
Preclinical Studies ◽  
Efficient Allocation ◽  
Allocation Of Resources ◽  
Preclinical Research ◽  
Replication Studies ◽  
Animal Models Of Disease ◽  
Models Of Disease

The purpose of preclinical research is to inform the development of novel diagnostics or therapeutics, and the results of experiments on animal models of disease often inform the decision to conduct studies in humans. However, a substantial number of clinical trials fail, even when preclinical studies have apparently demonstrated the efficacy of a given intervention. A number of large-scale replication studies are currently trying to identify the factors that influence the robustness of preclinical research. Here, we discuss replications in the context of preclinical research trajectories, and argue that increasing validity should be a priority when selecting experiments to replicate and when performing the replication. We conclude that systematically improving three domains of validity – internal, external and translational – will result in a more efficient allocation of resources, will be more ethical, and will ultimately increase the chances of successful translation.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health

2019 ◽  
Vol 26 (27) ◽  
pp. 5207-5229 ◽  
Author(s):  
Y.V. Madhavi ◽  
Nikhil Gaikwad ◽  
Veera Ganesh Yerra ◽  
Anil Kumar Kalvala ◽  
Srinivas Nanduri ◽  
...  
Keyword(s):  
Diabetic Complications ◽  
Energy Homeostasis ◽  
Cardiovascular Complications ◽  
Living System ◽  
Animal Models Of Disease ◽  
Beneficial Effects ◽  
Inflammatory Processes ◽  
Energy Sensing ◽  
Healthy Functioning ◽  
Models Of Disease

Adenosine 5′-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

Randomised Phase 1 clinical trials in oncology

2021 ◽  
Author(s):  
Alexia Iasonos ◽  
John O’Quigley
Keyword(s):  
Clinical Trials ◽  
Phase 1
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