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Prescribing errors are a source of preventable harm in healthcare, which may be mitigated using Electronic Prescribing (EP) systems. Anyone who routinely prescribes medication could benefit from digitally assisted automated checks to identify whether a prescription should potentially not be allowed (e.g. drug allergy). National Health Service (NHS) Trusts have implemented a range of EP systems; however, their performance has not hitherto been evaluated. We developed the web-based Electronic Prescribing Risk and Safety Evaluation (ePRaSE) tool, which comprises a bank of prescribing scenarios to evaluate the performance of EP systems. We solicited ePRaSE testing: 68 pharmacists from across 45 English NHS Trusts, utilising 13 different EP systems volunteered for the study. We found considerable variability in mitigation performance (systems correctly identifying risk of error when prescribing) across both NHS Trusts and EP systems. Moreover, we found that mitigation performance varied considerably across NHS Trusts using the same EP system, strongly suggesting there are opportunities to optimise performance within systems. The ePRaSE tool is effective in identifying variability in risk management between NHS Trusts and EP systems. Wider use of this tool may facilitate improvements in EP system configurations, thus minimising potential harm from prescribing errors. [ABSTRACT FROM AUTHOR]

Author(s): Madaiah Puttaraju [sup.1] , Michaela Jackson [sup.2] , Stephanie Klein [sup.2] , Asaf Shilo [sup.1] , C. Frank Bennett [sup.2] , Leslie Gordon [sup.3] [sup.4] , Frank Rigo [sup.2] [...], Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms. Treatment with an optimized lead candidate resulted in extension of lifespan in a mouse model of HGPS. Progerin mRNA levels were robustly reduced in vivo, but the extent of progerin protein reduction differed between tissues, suggesting a long half-life and tissue-specific turnover of progerin in vivo. These results identify a novel therapeutic agent for HGPS and provide insight into the HGPS disease mechanism. Optimized antisense oligonucleotides that can reduce progerin tissue expression in vivo pave the way for development of a novel therapeutic approach for Hutchinson-Gilford progeria syndrome.

Introduction The neuromuscular disease spinal muscular atrophy (SMA), affecting approximately 1 in 10,000 individuals, is the most common inherited cause of infant death (1). The most frequent and severe type [...], BACKGROUND. Spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge of baseline and drug-induced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments. METHODS. SMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies. RESULTS. SMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels. CONCLUSIONS. A normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs. FUNDING. SMA Foundation, SMART, NIH (R01-NS096770, R01-NS062869), Ionis Pharmaceuticals, and PTC Therapeutics. Biogen provided support for absolute real-time RT-PCR.

Direct delivery of therapeutics to the central nervous system (CNS) greatly expands opportunities to treat neurological diseases but is technically challenging. This opinion outlines principal technical aspects of direct CNS delivery via intracerebroventricular (ICV) or intrathecal (IT) injection to common nonclinical test species (rodents, dogs, and nonhuman primates) and describes procedure-related clinical and histopathological effects that confound interpretation of test article-related effects. Direct dosing is by ICV injection in mice due to their small body size, while other species are dosed IT in the lumbar cistern. The most frequent procedure-related functional effects are transient absence of lower spinal reflexes after IT injection or death soon after ICV dosing. Common procedure-related microscopic findings in all species include leukocyte infiltrates in CNS meninges or perivascular (Virchow-Robin) spaces; nerve fiber degeneration in the spinal cord white matter (especially dorsal and lateral tracts compressed by dosing needles or indwelling catheters), spinal nerve roots, and sciatic nerve; meningeal fibrosis at or near IT injection sites; hemorrhage; and gliosis. Findings typically are minimal to occasionally mild. Findings tend to be more severe and/or have a higher incidence in the spinal cord segments and spinal nerve roots at or close to the site of administration. [ABSTRACT FROM AUTHOR]