We compare the predictions of Horizon-AGN, a hydro-dynamical cosmological simulation that uses an adaptive mesh refinement code, to observational data in the redshift range 0 < z < 6. We study the reproduction, by the simulation, of quantities that trace the aggregate stellar-mass growth of galaxies over cosmic time: luminosity and stellar-mass functions, the star formation main sequence, rest-frame UV-optical-near infrared colours and the cosmic star-formation history. We show that Horizon-AGN, which is not tuned to reproduce the local Universe, produces good overall agreement with these quantities, from the present day to the epoch when the Universe was 5% of its current age. By comparison to Horizon-noAGN, a twin simulation without AGN feedback, we quantify how feedback from black holes is likely to help shape galaxy stellar-mass growth in the redshift range 0 < z < 6, particularly in the most massive galaxies. Our results demonstrate that Horizon-AGN successfully captures the evolutionary trends of observed galaxies over the lifetime of the Universe, making it an excellent tool for studying the processes that drive galaxy evolution and making predictions for the next generation of galaxy surveys.

Fabry disease is an X-linked lysosomal storage disorder caused by loss of alpha-galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of glycosphingolipids in multiple cells and tissues. FLT190, an investigational gene therapy, is currently being evaluated in a Phase 1/2 clinical trial in patients with Fabry disease (NCT04040049). FLT190 consists of a potent, synthetic capsid (AAVS3) containing an expression cassette with a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (AAV2/S3-FRE1-GLAco). For mouse studies FLT190 genome was pseudotyped with AAV8 for efficient transduction. Preclinical studies in a murine model of Fabry disease (Gla-deficient mice), and non-human primates (NHPs) showed dose-dependent increases in plasma α-Gal A with steady-state observed 2 weeks following a single intravenous dose. In Fabry mice, AAV8-FLT190 treatment resulted in clearance of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in plasma, urine, kidney, and heart; electron microscopy analyses confirmed reductions in storage inclusion bodies in kidney and heart. In NHPs, α-Gal A expression was consistent with the levels of hGLA mRNA in liver, and no FLT190-related toxicities or adverse events were observed. Taken together, these studies demonstrate preclinical proof-of-concept of liver-directed gene therapy with FLT190 for the treatment of Fabry disease.

We present constraints on the flat ΛCDM cosmological model through a joint analysis of galaxy abundance, galaxy clustering and galaxy-galaxy lensing observables with the Kilo-Degree Survey. Our theoretical model combines a flexible conditional stellar mass function, to describe the galaxy-halo connection, with a cosmological N-body simulation-calibrated halo model to describe the non-linear matter field. Our magnitude-limited bright galaxy sample combines 9-band optical-to-near-infrared photometry with an extensive and complete spectroscopic training sample to provide accurate redshift and stellar mass estimates. Our faint galaxy sample provides a background of accurately calibrated lensing measurements. We constrain the structure growth parameter S 8 = σ 8 √ Ω m /0.3 = 0.773 +0.028 −0.030 , and the matter density parameter Ω m = 0.290 +0.021 −0.017 . The galaxy-halo connection model adopted in the work is shown to be in agreement with previous studies. Our constraints on cosmological parameters are comparable to, and consistent with, joint '3 × 2pt' clustering-lensing analyses that additionally include a cosmic shear observable. This analysis therefore brings attention to the significant constraining power in the often-excluded non-linear scales for galaxy clustering and galaxy-galaxy lensing observables. By adopting a theoretical model that accounts for non-linear halo bias, halo exclusion, scale-dependent galaxy bias and the impact of baryon feedback, this work demonstrates the potential and a way forward to include non-linear scales in cosmological analyses.

Introduction: Gaucher disease (GD), one of the most common lysosomal storage disorders, is an autosomal recessive condition resulting from mutations in the GBA gene that codes for the b-glucocerebrosidase (GCase) enzyme. Over 90% of patients have type 1 GD, which is characterised by lipid engorged macrophages (known as Gaucher cells) in multiple organs, including spleen, liver and bone marrow, with no overt involvement of the central nervous system (CNS). The current standard of care for type 1 GD patients includes enzyme replacement therapy (ERT), which provides good overall therapeutic benefit. However, ERT is administered intravenously every other week, resulting in a high cumulative cost and a significant treatment burden. Furthermore, disease manifestations, such as pulmonary and skeletal disease, remain unresolved with ERT. Gene therapy is emerging as a very promising avenue of treatment for various monogenic disorders and has the potential to provide sustained levels of GCase enzyme expression after a single treatment. Here we have evaluated liver-directed gene therapy in vitro and in vivo for the treatment of GD. Methods: Adeno-associated virus (AAV) constructs were optimised to express full-length wild-type GCase protein (GBA AAV) and packaged in AAV8 capsids for in vivo mouse studies, or our novel AAVS3 capsid for in vitro studies in a human cell line. GCase activity was determined fluorometrically with 4-Methylumbelliferyl-β-D-glucopyranoside and activity was based on a 4-methylumbelliferone standard curve. Levels of GCase in plasma, and uptake in GD target organs were compared between our GBA AAV optimized construct and ERT treatment with velaglucerase alfa (VPRIV®) in C57BL/6 wild type mice. Doses used ranged from 2x109 to 2x1012 vg/kg for GBA AAV constructs and 60 U/kg for ERT. Results: Our initial proof of concept studies for liver-directed AAV gene therapy of GD used an AAV construct encoding the native full-length human GBA cDNA (RC-04-01). After a single intravenous injection into mice, RC-04-01 led to a dose-dependent expression of GCase in liver and robust levels of enzymatically active GCase in plasma. Based on these preliminary data, 37 GBA AAV constructs with optimisations to the coding sequence and changes to the promoter, signal peptide, and polyA sequences were designed and evaluated in vitro for GCase production. Among them, 6 constructs outperformed RC-04-01 and were further tested in mice. Construct RC-04-26 showed the highest GCase activity levels both in vivo and in vitro. At a dose of 2x1012 vg/kg, RC-04-26 showed plasma active GCase levels up to 9.4-fold higher than RC-04-01. Upon GBA AAV infusion, plasma GCase levels were steady and sustained for the duration of the entire study period (9 months). In addition, RC-04-26 infusion into mice resulted in robust uptake of GCase by cells in spleen, bone marrow and lung, demonstrating that liver-produced GCase is taken up by macrophages present in the GD target organs. Lastly, GCase bioavailability was evaluated after a single administration of RC-04-26 or ERT. With velaglucerase alfa, GCase was rapidly cleared from the bloodstream and tissues. However, RC-04-26 resulted in sustained and steady levels of GCase, with an overall bioavailability of GCase uptake over 170-fold higher than with ERT. Conclusions: Our current data support the hypothesis that a single administration of an optimised liver directed GBA AAV vector results in sustained elevation of GCase in the bloodstream and higher level of GCase bioavailability for uptake into macrophages than velaglucerase alfa. This observation supports further development of AAV gene therapy for Gaucher disease with the potential for enhanced therapeutic benefit from a one-off administration. Disclosures Miranda: Freeline Therapeutics: Employment, Equity Ownership. Canavese:Freeline Therapeutics: Employment, Equity Ownership. Chisari:Freeline Therapeutics: Employment, Equity Ownership. Pandya:Freeline: Employment, Equity Ownership. Cocita:Freeline Therapeutics: Employment, Equity Ownership. Portillo:Freeline: Employment, Equity Ownership. McIntosh:Freeline Therapeutics: Consultancy, Equity Ownership. Kia:Freeline Therapeutics: Employment, Equity Ownership. Foley:Freeline: Employment, Equity Ownership. Dane:Freeline: Employment, Equity Ownership. Jeyakumar:Freeline Therapeutics: Employment, Equity Ownership. Sheridan:Freeline Therapeutics: Employment, Equity Ownership. Corbau:Freeline: Employment, Equity Ownership. Nathwani:Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Flow through an in-vitro rigid model of the laryngeal channel is measured using pressure sensors, and visualized using the Schlieren technique for different geometrical configurations. A quasi-impulsive upstream flow condition is used to simulate the jet emerging from the glottis at phonation onset. The separated flow behaviour in the presence of a ventricular constriction ("false vocal folds") is examined. Direct numerical simulations are proposed to assess the aerodynamic effects of the ventricular bands on the dynamics of the flow patterns involved.