A direct, high throughput assay for Neutrophil extracellular traps (NETs) pharmaceutical industry, biotech/biomedical companies, autoimmune diseases
pharmaceutical industry, biotech/biomedical companies, autoimmune diseases
A direct, high throughput assay for Neutrophil extracellular traps (NETs)
Background:
Neutrophil extracellular traps (NETs) are immunogenic, extracellular DNA structures that harness important auto-antigens to be recognized by the adaptive immune system. Recent evidence suggests that NETs have a role in a number of noninfectious diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), diabetes, atherosclerosis and cancer. However, it is still unclear how and if NETs act as a common pathway in the pathophysiology of these clinically divergent autoimmune diseases. The exact role of NETs in these diseases remains to be elucidated and one limiting factor has been the lack of a well-defined assay to quantify NET formation. NETs are thought to play a role in the initiation of many noninfectious conditions, and, in combination with imaging NET production, this opens up the possibility of new therapies.
Technology Overview:
Researchers at LUMC have developed a direct, high throughput assay to quantifying NETs and are using this assay to study SLE and AAV patients. The assay directly visualizes and quantifies the amount of NETs produced on any given stimulus. The group at LUMC has a particular interest in autoimmune diseases, such as AAV and SLE). Any autoimmune diseases consist of periods of remission followed by episodes of disease activity (more about research and groups expertise can be found at http://www.einthovenlaboratory.com).
Benefits:
As the assay combines immunohistochemistry with quantification of extracellular DNA it provides an accurate assay that can be scaled up for high throughput.
Potential applications
This assay could be used as
- Diagnostic/ predictive test
- Clinical test of disease activity
- Ex vivo test for screening potential drugs
Further background:
http://www.nature.com
The Netherlands Epidemiology of Obesity (NEO) Study Database and Biobank obesity, metabolomic disease, biobank
obesity, metabolomic disease, biobank
The Netherlands Epidemiology of Obesity (NEO) Study Database and Biobank
Interested in conducting research on obesity and metabolic disease?
Leiden University Medical Center Netherlands has finished enrollment of the Epidemiology of Obesity Study (NEO). Information from 6,000 obese participants from the Netherlands was gathered over a four-year period with a goal of aiding researchers in their pursuit of causes and treatments for obesity and metabolic disease. Information ranging from health and depression questionnaires to heart and brain MRIs has been collected from 6,000 participants with a BMI = 27 kg/m2 or higher and 1,000 participants with a BMI <27 kg/m2.
Endpoints include diagnosis of Type 2 diabetes, cardiovascular disease, COPD, asthma, chronic kidney disease, osteoarthritis and all-cause mortality. Analyses were conducted on blood, serum, urine and plasma. Serum, DNA, RNA have been saved for future studies.
The database/biobank is now open for access. LUMC investigators involved in the NEO Study are also interested in research collaborations using the database/biobank.
For more information please find the link to the abstract and full publication here:
Abstract: The Netherlands Epidemiology of Obesity (NEO) study
Publication: The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection
ApoE3Leiden Mouse obesity, diabetes, Artherosclerosis, brown fat, metabolic disease
obesity, diabetes, Artherosclerosis, brown fat, metabolic disease
ApoE3Leiden Mouse
Apolipoprotein E is a constituent of VLDLs, chylomicrons, and HDLs and is essential for receptor-mediated uptake of remnant lipoproteins.
ApoE deficiency in mice leads to elevated plasma cholesterol levels that are due to the accumulation of remnant lipoproteins, and ApoE deficiency is associated with the development of atherosclerosis. In addition, these mice develop a fatty liver when fed normal chow and show a decreased VLDL-triglyceride secretion. In humans, the mutant ApoE3Leiden isoform is associated with a dominantly inherited form of familial dysbetalipoproteinemia.
The ApoE3Leiden gene contains a tandem repeat of codons 120 to 126, yielding a protein of 306 amino acids. Transgenic mice expressing ApoE3Leiden develop hyperlipidemia as a result of defective binding of E3Leiden-containing remnant lipoproteins to the LDL receptor and to the LDL receptor–related protein and are susceptible to diet-induced atherosclerosis.
Apolipoprotein E (ApoE)-deficient mice develop hepatic steatosis and show impaired very low density lipoprotein (VLDL)-triglyceride (TG) secretion. These effects are normalized with the introduction of the human ApoE3 gene. The APOE3Leiden mouse displays a human-like plasma lipid profile and is sensitive to diet-induced hyperlipidemia, obesity and insulin resistance as well as premature atherosclerosis.
Researchers at Leiden University Medical Center (LUMC) are interested in research collaborations using the ApoE3Leiden Mouse including crossbreeding to develop novel mouse models.
Type 1 Diabetes Neo-Epitopes: Autoimmunity Against a Defective Ribosomal Insulin Gene Product A new neo-epitope generated by defective ribosomal products (DRiPs) from the proinsulin gene.
A new neo-epitope generated by defective ribosomal products (DRiPs) from the proinsulin gene.
Type 1 Diabetes Neo-Epitopes: Autoimmunity Against a Defective Ribosomal Insulin Gene Product
Background
Type 1 diabetes (T1D) is an autoimmune disease where the immune system destroys the insulin-producing pancreatic beta cells. These cells are insulin factories dedicated to the maintenance of glucose homeostasis; insulin, stored in secretory granules, represents 10–15% of the protein content of these cells. Studies of samples from humans with T1D and mouse models of the disease indicate that native insulin and its precursors act as primary autoantigens, and fragments of the preproinsulin peptide have been identified as main targets of cytotoxic islet-autoreactive CD8+ T cells in human T1D. In autoimmune disease, there is increasing evidence that local inflammation or other forms of stress combined with genetic disposition leads to the generation and the accumulation of aberrant or modified proteins (neo-epitopes) to which central tolerance is lacking and thereby triggering autoimmunity. Until now, neo-epitopes have been shown to be generated through transcriptional, post-transcriptional and post-translational processes. However, an important class of neo-epitopes could be generated through non-conventional translational events and this technology is the first evidence of a naturally processed and presented epitope derived from nonconventional islet proteins.
Technology Overview
Scientists at Leiden University Medical Center have recently discovered a new neo-epitope generated by defective ribosomal products (DRiPs) from the proinsulin gene. Within the mRNA, the researchers have found an alternative open reading frame encoding a highly immunogenic polypeptide that is targeted by T cells in type 1 diabetes (T1D) patients. They show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and provide direct evidence that such CD8+ T cells are capable of killing human beta cells and thereby may be diabetogenic. This is the first evidence of a naturally processed and presented epitope derived from nonconventional islet proteins leading to the destruction of human beta cells by cytotoxic CD8+ T cells. They propose a new pathway of beta cell destruction by the immune system in which the generation of a neoepitope, such as INS-DRiP, plays a central role. Their findings support the emerging concept that beta cells are destroyed in T1D by a mechanism comparable to classical antitumour responses whereby the immune system has been trained to survey for dysfunctional cells in which errors have accumulated. This invention reveals a potential new mechanism underlying the pathology of T1D, and may allow the development of novel T1D diagnostics and therapies (Nat Med. 2017 Apr;23(4):501-507).
Details and State of Development:
Proof of concept.
Applications
- Novel T1D diagnostics
- Novel T1D therapies
Opportunity
- Research collaboration to further unravel the mechanism of INS-DriP formation
- Development of novel T1D diagnostics and therapies
ApoE3Leiden Mouse The APOE3Leiden mouse displays a human-like plasma lipid profile and is sensitive to diet-induced hyperlipidemia among other illnesses.
The APOE3Leiden mouse displays a human-like plasma lipid profile and is sensitive to diet-induced hyperlipidemia among other illnesses.
ApoE3Leiden Mouse
Background
ApoE deficiency in mice leads to elevated plasma cholesterol levels that are due to the accumulation of remnant lipoproteins, and ApoE deficiency is associated with the development of atherosclerosis. In addition, these mice develop a fatty liver when fed normal chow and show a decreased VLDL-triglyceride secretion. In humans, the mutant ApoE3Leiden isoform is associated with a dominantly inherited form of familial dysbetalipoproteinemia.
Technology Overview
The ApoE3Leiden gene contains a tandem repeat of codons 120 to 126, yielding a protein of 306 amino acids. Transgenic mice expressing ApoE3Leiden develop hyperlipidemia as a result of defective binding of E3Leiden-containing remnant lipoproteins to the LDL receptor and to the LDL receptor–related protein and are susceptible to diet-induced atherosclerosis. Apolipoprotein E (ApoE)-deficient mice develop hepatic steatosis and show impaired very low density lipoprotein (VLDL)-triglyceride (TG) secretion. These effects are normalized with the introduction of the human ApoE3 gene. The APOE3Leiden mouse displays a human-like plasma lipid profile and is sensitive to diet-induced hyperlipidemia, obesity and insulin resistance as well as premature atherosclerosis.
Details and State of Development:
- The ApoE3Leiden mouse has been used in numerous studies over the past decade
- Well validated model
Applications
- Studies for hyperlipidemia, atherosclerosis, obesity and insulin resistance
- Screening compounds for their effects on HDL levels
- Crossbreeding to develop novel mouse models for research use
Opportunity
Researchers at Leiden University Medical Center (LUMC) are interested in research collaborations using the ApoE3Leiden Mouse including crossbreeding to develop novel mouse models.
Keywords: obesity, diabetes, Artherosclerosis, brown fat, metabolic disease
The Netherlands Epidemiology of Obesity (NEO) Study Database and Biobank Information from 6,000 obese participants from the Netherlands was gathered over a four-year period with a goal of aiding researchers.
Information from 6,000 obese participants from the Netherlands was gathered over a four-year period with a goal of aiding researchers.
The Netherlands Epidemiology of Obesity (NEO) Study Database and Biobank
Technology Overview
Interested in conducting research on obesity and metabolic disease?
Leiden University Medical Center Netherlands has finished enrollment of the Epidemiology of Obesity Study (NEO). Information from 6,000 obese participants from the Netherlands was gathered over a four-year period with a goal of aiding researchers in their pursuit of causes and treatments for obesity and metabolic disease. Information ranging from health and depression questionnaires to heart and brain MRIs has been collected from 6,000 participants with a BMI = 27 kg/m2 or higher and 1,000 participants with a BMI < 27 kg/m2. Endpoints include diagnosis of Type 2 diabetes, cardiovascular disease, COPD, asthma, chronic kidney disease, osteoarthritis and all-cause mortality. Analyses were conducted on blood, serum, urine and plasma. Serum, DNA, RNA have been saved for future studies.
Details and State of Development:
Four-year enrollment period is complete; follow-up is on-going.
Applications
Collaborative studies on the effect of obesity on disease Access to data and samples for in-depth studies.
Opportunity
The database/biobank is now open for access. LUMC investigators involved in the NEO Study are also interested in research collaborations using the database/biobank.
Keywords: obesity, metabolomic disease, biobank
Novel alpha-Glucosidase and alpha-Galactosidase Inhibitors as Antidiabetic, Antiviral Drugs and as Pharmacological Chaperones for Pompe Disease Small molecules that react reversibly or irreversibly with human α-glucosidases depending on nitrogen position of the cyclic sulfamidate.
Small molecules that react reversibly or irreversibly with human α-glucosidases depending on nitrogen position of the cyclic sulfamidate.
Novel alpha-Glucosidase and alpha-Galactosidase Inhibitors as Antidiabetic, Antiviral Drugs and as Pharmacological Chaperones for Pompe Disease
Background
The global α-glucosidase inhibitors market generated $ 4069 million in 2018 and is expected to grow at a CAGR of 2% during 2019-2024. Acarbose, Miglitol, and Voglibose are the most prescribed alpha-glucosidase inhibitors used in the management of hyperglycemia for the treatment of type 2 diabetes mellitus. On the other hand, the combination of small α-glucosidase inhibitors as pharmacological chaperones (PCs) with enzyme replacement therapy (ERT) has shown a synergic effect in improved enzyme activity and reduction of toxic metabolites. Therefore, it is expected that the co-treatment PC-ERT may reduce the amount of ERT necessary to achieve the desired pharmacological effect and therefore may lower lysosomal storage diseases (LSDs) treatment cost. Current ERT is very costly, ranging between € 9 - € 10 million (£ 7.9 - £ 8.8 million, $ 13.0- $ 14. 5 million) during a patient's lifetime. No PC-ERT treatment for Pompe disease exists. Last but not least, recent studies have demonstrated that
ER α-glucosidases I and II are essential for the morphorgenesis of many enveloped viruses, and various iminosugar-based ER α-glucosidase inhibitors has shown in vivo antiviral efficacy in animals infected with Dengue, Ebola and influenza viruses.
Technology Overview
Leiden University have developed a new class of α-glucosidase inhibitors names α-cyclosulfamidates.
α-Glucosidase configured cyclosumaidates react reversibly or irreversibly with diverse human α-glucosidases depedning on the nitrogen position of the cyclic sulfamidate. They have shown that the reversible α-cyclosulfamidate is able to stabilize the recombinant lysosomal human α-glucosidase (GAA) in in vitro and in situ cell experiments and increased enzyme activity is observed in the medium of the cells co-treated with this α- cyclosulfamidate and recombinant GAA. Herein they describe the potential treatment of Diabetes and / or viral infections, as well as the potential of the reversible analogue as stabilizer of GAA for the treatment for Pompe patients in combination with ERT.
Applications
This invention provides a set of new α-glucosidase and α-galactosidase inhibitors. α-Glucosidase inhibitors have shown beneficial effects in multiple applications (antidiabetics, antiviral and as pharmacological chaperones for Pompe disease). Various combinations of enzyme replacement therapy or (mult) gene therapies with a pharmacological chaperone (glycosidase inhibitor) for the treatment of lysosomal storage diseases and glycosidase deficiency related diseases, particularly Fabry, Gaucher or Pompe disease. This combination optimizes the clinical benefit, ie, reduced enzyme treatment, while minimizing disadvantages associated with ERT.