CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.

Geographical variation and the determinants of domestic endotoxin levels in mattress dust in Europe

Endotoxin exposures have manifold effects on human health. The geographical variation and determinants of domestic endotoxin levels in Europe have not yet been extensively described. To investigate the geographical variation and determinants of domestic endotoxin concentrations in mattress dust in Europe using data collected in the European Community Respiratory Health Survey follow-up (ECRHS II). Endotoxin levels were measured in mattress dust from 974 ECRHS II participants from 22 study centers using an immunoassay. Information on demographic, lifestyle, and housing characteristics of the participants was obtained in face-to-face interviews. The median endotoxin concentration in mattress dust ranged from 772 endotoxin units per gram (EU/g) dust in Reykjavik, Iceland, to 4806 EU/g in Turin, Italy. High average outdoor summer temperature of study center, cat or dog keeping, a high household crowding index, and visible damp patches in the bedroom were significantly associated with a higher endotoxin concentrations in mattress dust. There is a large variability in domestic endotoxin levels across Europe. Average outdoor summer temperature of study center, which explains only 10% of the variation in domestic endotoxin level by center, is the strongest meteorological determinant. The observed variation needs to be taken into account when evaluating the health effects of endotoxin exposures in international contexts

Endotoxin levels in settled airborne dust in European schools : The HITEA school study

Indoor exposure to microbial agents is known to influence respiratory health. Besides home exposure, exposure in schools can affect respiratory health. In this study, we measured endotoxin in settled dust in primary schools in three European countries from three different geographical regions with different climates. Our aim was to characterize endotoxin levels in primary schools and evaluate associations with potential determinants. Endotoxin levels were repeatedly assessed in 23 schools in Spain (n = 7), the Netherlands (n = 10), and Finland (n = 6) using electrostatic dustfall collectors. In total, 645 measurements were taken in 237 classrooms. Endotoxin levels differed significantly between countries; Dutch schools had the highest levels, while Finnish schools showed the lowest levels. In each country, differences in endotoxin levels were observed between schools and over the sampling periods. Estimates improved after adjustment for sampling period. Factors affecting endotoxin levels in a school differed per country. In general, endotoxin levels were higher in lower grades and in classrooms with higher occupancy. School endotoxin levels may contribute significantly to total endotoxin exposure in children and teachers. As the correlation between the repeated measurements is reasonable, single endotoxin measurements form a reasonable basis for estimating annual endotoxin levels in schools

Influence of microstructure on the application of Ni-Mn-In Heuler compounds for multicaloric cooling using magnetic field and uniaxial stress.

Novel multicaloric cooling utilizing the giant caloric response of Ni-Mn-based metamagnetic shape-memory alloys to different external stimuli such as magnetic field, uniaxial stress and hydrostatic pressure is a promising candidate for energy-efficient and environmentally-friendly refrigeration. However, the role of microstructure when several external fields are applied simultaneously or sequentially has been scarcely discussed in literature. Here, we synthesized ternary Ni-Mn-In alloys by suction casting and arc melting and analyzed the microstructural influence on the response to magnetic fields and uniaxial stress. By combining SEM-EBSD and stress-strain data, a significant effect of texture on the stress-induced martensitic transformation is revealed. It is shown that a texture can strongly reduce the critical transformation stresses. The effect of grain size on the material failure is demonstrated and its influence on the magnetic-field-induced transformation dynamics is investigated. Temperature-stress and temperature-magnetic field phase diagrams are established and single caloric performances are characterized in terms of ΔsT and ΔTad. The cyclic ΔTad values are compared to the ones achieved in the multicaloric exploiting-hysteresis cycle. It turns out that a suction-cast microstructure and the combination of both stimuli enables outstanding caloric effects in moderate external fields which can significantly exceed the single caloric performances. In particular for Ni-Mn-In, the maximum cyclic effect in magnetic fields of 1.9 T is increased by more than 200 % to -4.1 K when a moderate sequential stress of 55 MPa is applied. Our results illustrate the crucial role of microstructure for multicaloric cooling using Ni-Mn-based metamagnetic shape-memory alloys