Exclusive symposium on NASH/Fibrosis challenges featuring key opinion leaders
Details: October 18, 2018; Hilton La Jolla / Torrey pines 10950N. Torrey Pines Rd. San Diego, CA 92037
Cisbio organized an exclusive seminar to bring together leading researchers interested by NAFLD and fibrosis to share ideas and discussing emerging developments in drug discovery.
Key industry leaders from across the globe were joined to this evening to discuss their recent and innovative scientific findings in the field of NAFLD.
Presentations have been followed by a wine tasting and networking opportunity under the stars on the Torreyana Terrace at the Hilton La Jolla, overlooking the beautiful grounds and patio space.
Manal F. Abdelmalek, MD, MPH
Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology, but long-term effect on fibrosis remains unknown. Treatment of underlying metabolic risks is recommended in clinical practice. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. Therefore, treatment of NASH will ultimately be impactful if there is regression of fibrosis lends improvement in liver-related morbidity and mortality. In 2018, a few phase 3 clinical trials for the treatment of NASH in progress. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies. Treatments which target the molecular pathways for fibrosis progression are of particular interest to decrease liver-related outcomes. Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD.
Professor Bart Staels, PhD
Non-Alcoholic Fatty Liver Disease (NAFLD) prevalence is increasing with the obesity pandemic. NAFLD encompasses a spectrum of liver disorders characterized by abnormal hepatic fat accumulation, inflammation and hepatocyte dysfunction. NAFLD predisposes susceptible individuals to cirrhosis, hepatocellular carcinoma and cardiovascular disease. Though the precise signals remain poorly understood, NAFLD pathogenesis likely involves the different hepatic cell types and multiple extra-hepatic signals. The complexity of the disease has been a major impediment to development of appropriate metrics of its progression and effective therapies. To identify the pathogenic mechanisms leading to the progression towards active non-alcoholic steatohepatitis (NASH) and fibrosis, we analyzed liver transcriptomes in human NASH patient cohorts. The transition from histologically-proven fatty liver to NASH and fibrosis was characterized by gene expression patterns which successively reflected altered functions in metabolism, inflammation and epithelial-mesenchymal transition. A meta-analysis combining our and public human transcriptomic data to murine models of NASH and fibrosis defined a molecular signature characterizing NASH and fibrosis and evidencing abnormal inflammation and extracellular matrix homeostasis. A pathway consistently perturbed in different studies during NAFLD progression is the Peroxisome proliferator-activated receptor (PPAR) pathway. PPARs regulate energy metabolism and are thus therapeutic targets in metabolic diseases such as, type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. Among hepatic PPAR targets, we identified dermatopontin expression which was found increased in fibrosis, decreased upon reversal of fibrosis after gastric bypass or after PPAR activation. Functional studies in mice identified an active role for dermatopontin in collagen deposition and fibrosis. Liver fibrotic histological damages are thus characterized by the deregulated expression of a restricted set of inflammation- and ECM-related genes. Future studies are needed to define the molecular pathways determining the 'natural progression' of NAFLD including key determinants of fibrosis and disease-related outcomes.
NAFLD is a complex and progressive disease involving a plurality of interactions between diverse cell types and cell signaling pathways. NAFLD is a complex disease stemming from steatosis and involving any degree of inflammation, stress, fibrosis or combination thereof. The multifaceted roots of the disease offer as many opportunities of therapeutic interventions. However, the study of NAFLD and characterization of lead compounds requires the use of multiple complex cell lines or even cocultures in 3D models that reproduce with lower biases organ state and disease etiology. These models and materials can be time intensive and costly. The selection of downstream technologies used as readouts to monitor biological changes in these precious samples is no longer as important. As the trueness in the evaluation of biomarkers impacts conclusions on drug development, the use of the right biological targets with highly validated tools/methods is critical. Cisbio's HTRF technology was developed to deliver the same information as regular methods in cell signaling analysis but with advanced specificity and validation and for the fraction of the overall cost and time. With a high commitment to meet customer needs and to deliver solutions that accelerate life science research, Cisbio has a large product portfolio in NAFLD and is continuously extending it by the addition of biological targets that are of primary importance in the disease, whatever the complexity of development of the tools. This presentation will encompass an overview of the HTRF core technology, the comparison with other techniques and the solutions available for life science research. Part of this presentation will focus on Cisbio's product pipeline for NAFLD research starting from biochemical nuclear receptor recruitment assays to hepatocyte ER stress, cellular HSC activation markers and ECM secreted Biomarkers. This overview will be done with a highlight on how far the tools are validated from the use of the most relevant cell models, the verification of specificity by siRNA experiments, up to the pharmaceutical validation using reference synthetic or biological compounds.
This event was designed to spark new idea, create engaging collaborations and provide inspiration to your work. We also would like to thank everyone who attended to this event and hope they enjoyed the presentations.
If you missed the symposium and want to learn more about the NAFLD/Fibrosis pathways download this guidebook that will provide you a 360° review of the disease pathways and mechanism.