Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.

Excellent results with cementless total hip arthroplasty and alumina-on-alumina pairing: minimum ten-year follow-up.

Ceramic-on-ceramic coupling is thought to be a durable alternative to metal- or alumina-on-polyethylene pairing. No evidence exists suggesting superior clinical and radiological results for hydroxyapatite-coated stems versus uncoated stems. The aim of this study is to report the performance of an alumina-on-alumina bearing cementless total hip arthroplasty and to compare stems with a tapered design with and without hydroxyapatite coating. We prospectively analysed the results of cementless tapered femoral stems (40 hydroxyapatite-coated versus 22 uncoated stems), a metal-backed fibre mesh hydroxyapatite-coated socket and alumina-on-alumina pairing. Of 75 hips studied, 62 were available for follow-up (mean of 10.5 years after surgery). The average Harris hip score was 90. Only one hydroxyapatite-coated stem was revised for aseptic loosening. One instance of non-progressive osteolysis was detected around a screw of a cup. All other components showed radiographic signs of stable ingrowth. Hydroxyapatite coating of the stem had no significant impact on the clinical or radiological results. Total hip arthroplasty with the presented implant and pairing provides a durable standard for all patients requiring hip joint replacement against which all newer generations of cementless implants should be judged.