Rescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase.

Pompe disease is a neuromuscular disorder caused by disease-associated variants in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA), which converts lysosomal glycogen to glucose. We previously reported full rescue of Pompe disease in symptomatic 4-month-old Gaa knockout (Gaa-/-) mice by adeno-associated virus (AAV) vector-mediated liver gene transfer of an engineered secretable form of GAA (secGAA). Here, we showed that hepatic expression of secGAA rescues the phenotype of 4-month-old Gaa-/- mice at vector doses at which the native form of GAA has little to no therapeutic effect. Based on these results, we then treated severely affected 9-month-old Gaa-/- mice with an AAV vector expressing secGAA and followed the animals for 9 months thereafter. AAV-treated Gaa-/- mice showed complete reversal of the Pompe phenotype, with rescue of glycogen accumulation in most tissues, including the central nervous system, and normalization of muscle strength. Transcriptomic profiling of skeletal muscle showed rescue of most altered pathways, including those involved in mitochondrial defects, a finding supported by structural and biochemical analyses, which also showed restoration of lysosomal function. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA.This work was supported by Genethon, the French Muscular Dystro-phy Association (AFM), and Spark Therapeutics. It was also sup-ported by the European Union’s Research and Innovation Programunder grant agreement number 667751 (to F.M.), the EuropeanResearch Council Consolidator Grant under grant agreement number617432 (to F.M.), and Marie Skłodowska-Curie Actions-IndividualFellowship (MSCA-IF) grant agreement number 797144 (to U.C.)S

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2)

Objective- To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods- This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results- Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. Conclusions- The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma