To evaluate the intraobserver and interobserver agreement for bone marrow burden (BMB) scores for individual examinations and for the change in BMB score over time in the same patient.A total of 119 sets of MR images of the lumbar spine and femora from 60 patients with Gaucher disease were included. Each set of MR images was scored using the BMB score independently by two experienced MSK radiologists. One radiologist performed a second read four weeks later. Intraobserver and interobserver agreement was assessed using Bland-Altman analysis and weighted kappa scores.BMB scores (n = 119) demonstrated fair intraobserver agreement (weighted kappa = 0.53) with a mean difference of − 0.20 and 95% limits of agreement (LOA) of (− 3.41, 3.01). Inter observer agreement was poor with weighted kappa 0.28 with mean difference of − 0.16 and 95% LOA of (− 4.45, 4.11).Change in BMB scores over time (n = 59) demonstrated poor/fair intraobserver agreement (weighted kappa 0.41, mean difference − 0.20 and 95% LOA (− 4.35, 3.94)). Interobserver agreement was poor (weighted kappa 0.25, mean difference − 0.12 with wide 95% LOA (− 6.23, 5.99)).Significant interobserver, and to a lesser extent intraobserver, variation occurs with blinded BMB scoring of Gaucher disease.

Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.

La presente divulgation concerne des lipides amines et des compositions les impliquant. Les compositions nanoparticulaires comprennent un lipide amine ainsi que d'autres lipides tels que des phospholipides, des lipides structuraux, des lipides PEG, ou une combinaison de ceux-ci. Des compositions nanoparticulaires comprenant en outre des agents therapeutiques et/ou prophylactiques tels que l'ARN qui sont utiles dans l'administration d'agents therapeutiques et/ou prophylactiques a des cellules ou des organes de mammiferes, par exemple, pour reguler l'expression de polypeptides, de proteines, ou de genes sont en outre decrites.