In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.

Gene-editing technologies, which include the CRISPR-Cas nucleases and CRISPR base editors, have the potential to permanently modify disease-causing genes in patients. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis).

The Development of Minitablets for a Pediatric Dosage Form for a Combination Therapy.

Minitablets are an appealing option for an age-appropriate pediatric dosage form. In particular, for combination therapies where multiple active ingredients are dosed simultaneously, the use of minitablets will enable independent adjustments of each dose. The work presented describes the development of Compound A and Compound B minitablets for a combination therapy.

Possibilities and Limiting Factors for the Use of Dissolution as a Quality Control Tool to Detect Presence of Crystallinity for Amorphous Solid Dispersions: An Experimental and Modeling Investigation.

In this article, experiments on tablets containing a model compound, grazoprevir, were conducted to explore how media selection for a quality control dissolution method can influence the sensitivity for the dissolution method toward drug crystallinity detection in an amorphous solid dispersion formulation. The experiment shows that under ideal nonsink conditions with respect to crystalline solubility, dissolution can indeed be predictive of crystallinity in the formulation. However, the limit of detection for crystallinity with quality control dissolution can change based on inherent variabilities in the drug product.

In microfluidico: Recreating in vivo hemodynamics using miniaturized devices.

Microfluidic devices create precisely controlled reactive blood flows and typically involve: (i) validated anticoagulation/pharmacology protocols, (ii) defined reactive surfaces, (iii) defined flow-transport regimes, and (iv) optical imaging. An 8-channel device can be run at constant flow rate or constant pressure drop for blood perfusion over a patterned collagen, collagen/kaolin, or collagen/tissue factor (TF) to measure platelet, thrombin, and fibrin dynamics during clot growth. A membrane-flow device delivers a constant flux of platelet agonists or coagulation enzymes into flowing blood.

A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus solute transport and local thrombin activity.

Hemostatic thrombi formed after a penetrating injury have a distinctive structure in which a core of highly activated, closely packed platelets is covered by a shell of less-activated, loosely packed platelets. We have shown that differences in intrathrombus molecular transport emerge in parallel with regional differences in platelet packing density and predicted that these differences affect thrombus growth and stability. Here we test that prediction in a mouse vascular injury model.