Cambridge Healthtech Instituteの第5回年次
Fibrosis and Inflammation
PLENARY KEYNOTE PROGRAM
Plenary Keynote Introduction (Sponsorship Opportunity Available)10:45 am
PLENARY: The New Science of Therapeutics
I will share reflections on how new paradigms in the science of therapeutics are creating opportunities to approach historic challenges in medicine. Specifically, I will share approaches to targeting transcription factors and discuss how modularity is a paradigm for next-generation low-molecular weight and biological therapeutics. Finally, I will offer reflections on drug development and the fitness, opportunities, and challenges of the biomedical ecosystem.
PLENARY: Accelerating Drug Discovery Using Machine Learning and Cell Painting Images
Microscopy images can reveal whether a cell is diseased, is responding to a drug treatment, or whether a pathway has been disrupted by a genetic mutation. In a strategy called image-based profiling, often using the Cell Painting assay, we extract hundreds of features of cells from images. Just like transcriptional profiling, the similarities and differences in the patterns of extracted features reveal connections among diseases, drugs, and genes.
Enjoy Lunch on Your Own12:25 pm
Welcome Remarks1:45 pm
LIVER FIBROSIS AND NASH
FEATURED PRESENTATION: Targeting Liver Fibrosis
Targeting Activated Macrophages to Improve Liver Cirrhosis: the Discovery and Clinical Translation of Belapectin
Galectin-3 is a major driver of tissue inflammation and fibrosis. It is produced by activated macrophages and secreted in the extracellular matrix where it interacts with macromolecules and cells to form a fibrosome. In chronic liver inflammation, peripheral macrophages invade the organ and may lead to cirrhosis, a life-threatening fibrotic disorder. Belapectin, a large molecule captured by macrophages, is a galectin-3 inhibitor in development for cirrhosis.
Targeted gene therapy delivery of suitable constructs can enable the safe and rapid clearance of a toxic excess of intracellular cholesterol. This clearance is sufficient in and of itself to reverse the inflammatory, fibrotic pathology associated with conditions such as non-alcoholic steatohepatitis (NASH), in which a localized excess of cholesterol plays an important role.
Refreshment Break in the Exhibit Hall with Poster Viewing3:25 pm
Close of Day8:00 pm
Registration and Morning Coffee7:30 am
TARGETING FIBROBLASTS (SOMETIMES IN THE TME)
Selectively Targeting TGF-β for Antifibrotic Drug Development
I will highlight the discovery and development of Bexotegrast, a dual selective integrin inhibitor for pulmonary fibrosis. I will also describe Pliant’s translational approach and successful Phase 2 results in IPF.
Stromal Targeting for Fibrotic and Neoplastic Disease
We used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophage population to which we assign a profibrotic role across species and tissues, which are defined by expression of SPP1, GPNMB,FABP5, and CD63. GM-CSF, IL-17A or TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers, and blockade of these cytokines reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis in mice.
Translational Pharmacology of Oral and Inhaled Small Molecule Galectin-3 Inhibitors for Liver and Lung Fibrosis
Galectin-3 is a ß-galactoside-binding lectin highly expressed in fibrotic tissue of diverse etiologies and has been shown to play a key role in lung and liver fibrosis. Galecto has developed several galectin-3 clinical candidates with disease-tailored administration for lung and liver fibrosis. This talk will focus on:
- an introduction to the Galecto portfolio of galectin inhibitors
- bioinformatic analysis constructing pathway maps depicting the role of galectin-3 in fibrosis with confirmatory overlaid inhibitor profiles
- translational pharmacology of inhaled and oral clinical candidates in IPF and cirrhosis including Phase II clinical data
Transforming Growth Factor Beta (TGFß) as a Small-Molecule Target for IO and for Fibrosis
Fibrosis is an intrinsic response to chronic injury and can progress toward excessive tissue scarring and organ failure, such as idiopathic pulmonary fibrosis (IPF) and liver cirrhosis. TGF-ß1 and 3 are key cytokines involved in the pathogenesis of tissue fibrosis. Targeting avb6 for IPF and biliary liver fibrosis is supported by preclinical pharmacological inhibition and genetic ablation data. However, TGF-ß inhibition is also linked to epithelial cell proliferation and inflammation.
In-Person Group Discussions10:05 am
Coffee Break in the Exhibit Hall with Poster Viewing10:50 am
The Vasculature in Fibrosis: Bystander or Active Participant?
Evidence is accumulating that there are abnormalities in the pulmonary endothelium of patients with idiopathic pulmonary fibrosis (IPF), such as increased vascular permeability, loss of capillaries, and expansion of bronchial vessels. Single-cell RNA sequencing (scRNAseq) of IPF lung tissue suggests a loss of capillary endothelial cells (EC) in the fibrotic lung, and expansion of other EC. Defining the EC abnormalities present in IPF may identify opportunities for therapeutic intervention.
A Lung-Regenerative, Caveolin-Targeted Peptide for IPF
LTI-03 is a caveolin-1 scaffolding domain (CSD) peptide formulated for dry powder inhalation in idiopathic pulmonary fibrosis (IPF) patients. The anti-fibrotic and lung-regenerative effects of LTI-03 were confirmed in several experimental and translational studies including IPF precision-cut lung slices (PCLS). In PCLS studies, LTI-03 matched the potent anti-fibrotic effects of nintedanib without the toxicity and necrosis observed with the standard-of-care drug. LI-03 also enhanced alveolar epithelium viability. Inhaled LTI-03 was well tolerated in normal volunteers (NCT04233814) and a Phase 1b clinical trial is now underway in IPF patients. Together, LTI-03 is an exciting new IPF therapy.
Sponsored Presentation (Opportunity Available)12:30 pm
Transition to Lunch1:00 pm
Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:05 pm
Dessert Break in the Exhibit Hall with Last Chance for Poster Viewing1:35 pm
INFLAMMATION AND FIBROSIS OF THE GUT AND OTHER ORGANS
Anti-Fibrotic Efficacy of ACC2 Inhibition in Preclinical Models of Hepatic and Cardiac Fibrosis
TLC-3595 is a first-in-class, potent, systemically-distributed, oral, allosteric acetyl-CoA carboxylase 2 (ACC2)-selective inhibitor. TLC-3595 has pleiotropic benefits in multiple cell types that contribute to anti-fibrotic effects in murine models of hepatic fibrosis, and also reduces cardiac fibrosis and improves mortality in a genetic model of heart failure by restoring impaired fatty acid oxidation. These observations support the evaluation of TLC-3595 in patients with metabolic disease, including diabetes, NASH and cardiovascular disease.
Close of Conference4:20 pm