Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A.

Background: Severe hemophilia A is managed with factor VIII replacement or hemostatic products that stop or prevent bleeding. Data on gene therapy with hematopoietic stem-cell (HSC)-based expression of factor VIII for the treatment of severe hemophilia A are lacking.

Methods: We conducted a single-center study involving five participants 22 to 41 years of age with severe hemophilia A without factor VIII inhibitors.

Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation.

Host-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacterial defence against bacteriophages. Here we characterize the widely distributed anti-phage defence system CmdTAC, which provides robust defence against infection by the T-even family of phages.

Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.

Background: Hemophilia A arises from dysfunctional or deficient coagulation factor (F)VIII and leads to inefficient fibrin clot formation and uncontrolled bleeding events. The development of antibody inhibitors is a clinical complication in hemophilia A patients receiving FVIII replacement therapy. LE2E9 is an anti-C1 domain inhibitor previously isolated from a mild/moderate hemophilia A patient and disrupts FVIII interactions with von Willebrand factor and FIXa, though the intermolecular contacts that underpin LE2E9-mediated FVIII neutralization are undefined.

Mechanism of phage sensing and restriction by toxin-antitoxin-chaperone systems.

Toxin-antitoxins (TAs) are prokaryotic two-gene systems composed of a toxin neutralized by an antitoxin. Toxin-antitoxin-chaperone (TAC) systems additionally include a SecB-like chaperone that stabilizes the antitoxin by recognizing its chaperone addiction (ChAD) element. TACs mediate antiphage defense, but the mechanisms of viral sensing and restriction are unexplored.