A5051337483- Fibroblast Growth Factor Research
- Kruppel-like factors research
- Liver Disease Diagnosis and Treatment
- Genomics, phytochemicals, and oxidative stress
- Chromatin Remodeling and Cancer
- Genetics, Aging, and Longevity in Model Organisms
- Diet, Metabolism, and Disease
- Cancer Mechanisms and Therapy
- Epigenetics and DNA Methylation
- Glutathione Transferases and Polymorphisms
- Chronic Myeloid Leukemia Treatments
- Endoplasmic Reticulum Stress and Disease
- Diet and metabolism studies
- CRISPR and Genetic Engineering
- Peptidase Inhibition and Analysis
- Nuclear Receptors and Signaling
- Histone Deacetylase Inhibitors Research
- Liver Disease and Transplantation
- Hepatitis C virus research
- Metabolism, Diabetes, and Cancer
- Eosinophilic Disorders and Syndromes
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Biochemical Analysis and Sensing Techniques
- Receptor Mechanisms and Signaling
Spero Therapeutics (United States)
2020-2024
Massachusetts Institute of Technology
2014-2019
Whitehead Institute for Biomedical Research
2015
Williams College
2010-2014
Harvard University
2011-2013
Dana-Farber Cancer Institute
2011-2013
Boston Children's Hospital
2013
Boston Children's Museum
2012
Children's Hospital
2012
Palmetto Hematology Oncology
2012
Catecholaminergic polymorphic ventricular tachycardia is a form of exercise-induced sudden cardiac death that has been linked to mutations in the Ca2+ release channel/ryanodine receptor (RyR2) located on sarcoplasmic reticulum (SR). We have shown catecholaminergic tachycardia-linked RyR2 significantly decrease binding affinity for calstabin-2 (FKBP12.6), subunit stabilizes closed state channel. proposed RyR2-mediated diastolic SR leak triggers (VT) and death. In calstabin-2-deficient mice,...
Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these established, dynamically maintained, and subsequently contribute control poorly understood. The switch/sucrose non-fermentable chromatin remodeling complex, also known as Brg1 associated factors is a master developmental regulator tumor suppressor capable of mobilizing nucleosomes in biochemical assays. its role establishing nucleosome...
Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)–scavenging enzymes drug efflux pumps, but how these genes up-regulated in response to de-differentiation is not known. Here, we examine this question using global transcriptional profiling identify ROS-induced already cells, even the absence of oxidative damage. Using approach, found Nrf2...
Experimental fibroblast growth factor 21 (FGF21) analogs can improve lipid profiles in patients with metabolic diseases. However, their effects on markers of insulin sensitivity appear to be minimal, potentially because insufficient exposure. Systemic drug levels vary from sub-pharmacological demonstrating pharmacodynamic but dose-limiting adverse events. Here we report results a phase 1 multiple ascending dose study AKR-001, an Fc-FGF21 fusion protein engineered for sustained systemic...
Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess safety tolerability efruxifermin compensated NASH cirrhosis.Patients stage 4 fibrosis (n = 30) were randomized 2:1 receive 50 mg 20) or placebo 10) once-weekly for 16 weeks. endpoint efruxifermin. Secondary exploratory endpoints included evaluation non-invasive markers liver injury fibrosis, glucose lipid metabolism,...
Background & AimsIn phase 2 studies, efruxifermin, an Fc–FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated (MASH), for which there is no approved treatment. Type diabetes (T2D) obesity are prevalent among MASH increasingly treated glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety efficacy of efruxifermin MASH, fibrosis, T2D taking a...
The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates immunity C. through phosphorylation CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken genomic analysis transcriptional response infection by Pseudomonas aeruginosa, combining genome-wide expression RNA-seq with...
High-fructose diets have been implicated in obesity via impairment of leptin signaling humans and rodents. We investigated whether fructose-induced resistance mice could be used to study the metabolic consequences fructose consumption humans, particularly children adolescents. Male C57Bl/6 were weaned a randomly assigned diet: high fructose, sucrose, fat, or control (sugar-free, low-fat). Mice maintained on their for at least 14 weeks. While fructose-fed regularly consumed more kcal expended...
Emerging evidence demonstrates that subunits of the SWI/SNF chromatin remodeling complex are specifically mutated at high frequency in a variety human cancer types. SNF5 (SMARCB1/INI1/BAF47), core subunit complex, is inactivated vast majority rhabdoid tumors (RT), an aggressive type pediatric cancer. SNF5-deficient cancers diploid and genomically stable, suggesting epigenetically based changes transcription key drivers tumor formation caused by loss. However, there limited understanding...
Animals have evolved critical mechanisms to maintain cellular and organismal proteostasis during development, disease, exposure environmental stressors. The Unfolded Protein Response (UPR) is a conserved pathway that senses responds the accumulation of misfolded proteins in endoplasmic reticulum (ER) lumen. We previously demonstrated IRE-1-XBP-1 branch UPR required Caenorhabditis elegans ER homeostasis larval development presence pathogenic Pseudomonas aeruginosa In this study, we identify...
Efruxifermin (EFX) is a homodimeric human IgG
Introduction & Objective: In phase 2 studies, efruxifermin (EFX), a long-acting bivalent Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with metabolic dysfunction-associated (MASH). Many MASH have type diabetes (T2D), which is increasingly treated glucagon-like peptide-1 receptor agonists (GLP-1RAs). We investigated the effects of EFX T2D, including those being GLP-1RAs. Methods: The on markers insulin sensitivity glycemic control were studied 5...
Analogues of fibroblast growth factor 21 (FGF21) demonstrate diverse metabolic benefits in preclinical models type 2 diabetes, dyslipidaemia and non-alcoholic steatohepatitis (NASH), but clinical responses with different analogues are inconsistent. Efruxifermin is an Fc-FGF21 fusion protein prolonged half-life enhanced receptor affinity compared native human FGF21. trials for the treatment steatohepatitis.Efruxifermin was administered weekly to male female Sprague Dawley rats 4 or 26 weeks....
Abstract SNF5 (SMARCB1/INI1/BAF47), a core subunit of SWI/SNF chromatin remodeling complexes, is potent tumor suppressor that specifically inactivated in variety aggressive pediatric cancers. We have recently demonstrated acts as not genetically via maintenance genome integrity, but epigenetically transcriptional regulation. However, few the target genes essential for oncogenesis following loss been identified. Here, we demonstrate aberrant epigenetic silencing gene BIN1 conserved event...
Abstract Efruxifermin (EFX) is a novel Fc-fusion analog of human fibroblast growth factor 21 (FGF21), currently in clinical development as potential treatment for non-alcoholic steatohepatitis (NASH). Each molecule EFX consists two modified FGF21 molecules, each attached at their N-termini to IgG1 Fc domain by short polyglycine-serine linker. The moiety incorporates three amino acid substitutions (L98R, P171G, and A180E relative native FGF21). Two these are proximal the C-terminus (P171G...
Abstract Tumor recurrence and metastasis underlie the majority of cancer-related deaths. Cancer cells that recur or metastasize are often both de-differentiated multidrug resistant, but mechanistic basis for this has been poorly understood. We have recently shown de-differentiation promotes resistance by activating Nrf2, which stimulates transcription drug efflux pumps enzymes scavenge reactive oxygen species (ROS). De-differentiation activates Nrf2 a non-canonical mechanism involving its...
Chronic 60% fructose feeding decreases the sensitivity to leptin in rats as assessed by food intake and body weight after administration of exogenous leptin. We hypothesized that a diet would also lead resistance mice, 1) lack response leptin, 2) elevated circulating 3) entry into torpor upon fasting. Male Hsd:NSA(CF‐1) mice were fed either or an isocaloric fructose‐free monitored. After 4 weeks diet, injected intraperitoneally with (5 mg/kg) consequent changes 8 more on plasma levels...
Abstract The nematode Caenorhabditis elegans has emerged as a genetically tractable animal host in which to study evolutionarily conserved mechanisms of innate immune signaling. We previously showed that the PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway regulates immunity C. through phosphorylation CREB/ATF bZIP transcription factor, ATF-7. Here, we have undertaken genomic analysis transcriptional response infection by Pseudomonas aeruginosa , combining genome-wide expression...
A third of patients with type 2 diabetes (T2D) are estimated to have nonalcoholic steatohepatitis (NASH). There is a high unmet need for safe and effective therapies that can address liver health metabolic comorbidities in NASH patients. Efruxifermin (EFX), long-acting Fc-FGF21 fusion protein, demonstrated robust reductions fat content, markers injury fibrosis, improved lipid glucose metabolism fibrosis stage 1-3.1Patients (N=80) were randomized receive placebo or 28, 50, 70mg EFX 16 weeks,...