Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Measurement of H Λ 4 and He Λ 4 binding energy in Au+Au collisions at s NN = 3 GeV

Measurements of mass and Λ binding energy of Λ4H and Λ4He in Au+Au collisions at sNN=3 GeV are presented, with an aim to address the charge symmetry breaking (CSB) problem in hypernuclei systems with atomic number A = 4. The Λ binding energies are measured to be 2.22±0.06(stat.)±0.14(syst.) MeV and 2.38±0.13(stat.)±0.12(syst.) MeV for Λ4H and Λ4He, respectively. The measured Λ binding-energy difference is 0.16±0.14(stat.)±0.10(syst.) MeV for ground states. Combined with the γ-ray transition energies, the binding-energy difference for excited states is −0.16±0.14(stat.)±0.10(syst.) MeV, which is negative and comparable to the value of the ground states within uncertainties. These new measurements on the Λ binding-energy difference in A = 4 hypernuclei systems are consistent with the theoretical calculations that result in ΔBΛ4(1exc+)≈−ΔBΛ4(0g.s.+)<0 and present a new method for the study of CSB effect using relativistic heavy-ion collisions

Electric-charge-dependent directed flow splitting of produced quarks in Au+Au collisions

We report directed flow (v1) of multistrange baryons (Ξ and Ω) and improved v1 data for K−, p¯, Λ¯ and ϕ in Au+Au collisions at sNN=27 and 200 GeV from the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). We focus on particles whose constituent quarks are not transported from the incoming nuclei but instead are produced in the collisions. At intermediate impact parameters, we examine quark coalescence behavior for particle combinations with identical quark content, and search for any departure from this behavior (“splitting”) for combinations having non-identical quark content. Under the assumption of quark coalescence for produced quarks, the splitting strength appears to increase with the electric charge difference of the constituent quarks in the combinations, consistent with electromagnetic effect expectations

Measurements of charged-particle multiplicity dependence of higher-order net-proton cumulants in p + p collisions at s = 200 GeV from STAR at RHIC

We report on the charged-particle multiplicity dependence of net-proton cumulant ratios up to sixth order from s=200 GeV p+p collisions at the Relativistic Heavy Ion Collider (RHIC). The measured ratios C4/C2, C5/C1, and C6/C2 decrease with increased charged-particle multiplicity and rapidity acceptance. Neither the Skellam baselines nor PYTHIA8 calculations account for the observed multiplicity dependence. In addition, the ratios C5/C1 and C6/C2 approach negative values in the highest-multiplicity events, which implies that thermalized QCD matter may be formed in p+p collisions

Energy dependence of polarized γγ→e+e− in peripheral Au+Au collisions at sNN=54.4 and 200 GeV with the STAR experiment at RHIC

We report the differential yields at mid-rapidity of the Breit-Wheeler process (γγ→e+e-) in peripheral Au+Au collisions at sNN=54.4 and 200 GeV with the STAR experiment at the Relativistic Heavy Ion Collider (RHIC), as a function of energy sNN, e+e- transverse momentum pT, pT2, invariant mass Mee, and azimuthal angle. In the invariant mass range of 0.

Light nuclei femtoscopy and baryon interactions in 3 GeV Au+Au collisions at RHIC

We report the measurements of proton-deuteron (p-d) and deuteron-deuteron (d-d) correlation functions in Au+Au collisions at sNN = 3 GeV using fixed-target mode with the STAR experiment at the Relativistic Heavy-Ion Collider (RHIC). For the first time, the source size (RG), scattering length (f0), and effective range (d0) are extracted from the measured correlation functions with a simultaneous fit. The spin-averaged f0 for p-d and d-d interactions are determined to be -5.28 ± 0.11(stat.) ± 0.82(syst.) fm and -2.62 ± 0.02(stat.) ± 0.24(syst.) fm, respectively. The measured p-d interaction is consistent with theoretical calculations and low-energy scattering experiment results, demonstrating the feasibility of extracting interaction parameters using the femtoscopy technique. The reasonable agreement between the experimental data and the calculations from the transport model indicates that deuteron production in these collisions is primarily governed by nucleon coalescence

Production of protons and light nuclei in Au+Au collisions at sNN=3 GeV with the STAR detector

We report the systematic measurement of protons and light nuclei production in Au+Au collisions at sNN=3GeV by the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). The transverse momentum (pT) spectra of protons (p), deuterons (d), tritons (t), He3, and He4 have been measured from midrapidity to target rapidity for different collision centralities. We present the rapidity and centrality dependence of particle yields (dN/dy), average transverse momentum ((pT)), yield ratios (d/p, t/p,He3/p, He4/p), as well as the coalescence parameters (B2, B3). The 4π yields for various particles are determined by utilizing the measured rapidity distributions, dN/dy. Furthermore, we present the energy, centrality, and rapidity dependence of the compound yield ratios (Np×Nt/Nd2) and compare them with various model calculations. The physics implications of these results on the production mechanism of light nuclei and the QCD phase structure are discussed

Reaction plane correlated triangular flow in Au+Au collisions at sNN=3 GeV

We measure triangular flow relative to the reaction plane at 3 GeV center-of-mass energy in Au+Au collisions at the BNL Relativistic Heavy Ion Collider. A significant v3 signal for protons is observed, which increases for higher rapidity, higher transverse momentum, and more peripheral collisions. The triangular flow is essentially rapidity-odd with a slope at midrapidity, dv3/dy|(y=0), opposite in sign compared to the slope for directed flow. No significant v3 signal is observed for charged pions and kaons. Comparisons with models suggest that a mean field potential is required to describe these results, and that the triangular shape of the participant nucleons is the result of stopping and nuclear geometry

Correlations of event activity with hard and soft processes in p+Au collisions at sNN=200 GeV at the RHIC STAR experiment

With the STAR experiment at the BNL Relativistic Heavy Ion Collider, we characterize sNN=200GeV p+Au collisions by event activity (EA) measured within the pseudorapidity range ηϵ[-5,-3.4] in the Au-going direction and report correlations between this EA and hard- and soft-scale particle production at midrapidity (ηϵ[-1,1]). At the soft scale, charged particle production in low-EA p+Au collisions is comparable to that in p+p collisions and increases monotonically with increasing EA. At the hard scale, we report measurements of high transverse momentum (pT) jets in events of different EAs. In contrast with the soft particle production, high-pT particle production and EA are found to be inversely related. To investigate whether this is a signal of jet quenching in high-EA events, we also report ratios of pT imbalance and azimuthal separation of dijets in high- and low-EA events. Within our measurement precision, no significant differences are observed, disfavoring the presence of jet quenching in the highest 30% EA p+Au collisions at sNN=200GeV

Drug discovery: Insights from the invertebrate Caenorhabditis elegans

Therapeutic drug development is a long, expensive, and complex process that usually takes 12–15 years. In the early phases of drug discovery, in particular, there is a growing need for animal models that ensure the reduction in both cost and time. Caenorhabditis elegans has been traditionally used to address fundamental aspects of key biological processes, such as apoptosis, aging, and gene expression regulation. During the last decade, with the advent of large-scale platforms for screenings, this invertebrate has also emerged as an essential tool in the pharmaceutical research industry to identify novel drugs and drug targets. In this review, we discuss the reasons why C. elegans has been positioned as an outstanding cost-effective option for drug discovery, highlighting both the advantages and drawbacks of this model. Particular attention is paid to the suitability of this nematode in large-scale genetic and pharmacological screenings. High-throughput screenings in C. elegans have indeed contributed to the breakthrough of a wide variety of candidate compounds involved in extensive fields including neurodegeneration, pathogen infections and metabolic disorders. The versatility of this nematode, which enables its instrumentation as a model of human diseases, is another attribute also herein underscored. As illustrative examples, we discuss the utility of C. elegans models of both human neurodegenerative diseases and parasitic nematodes in the drug discovery industry. Summing up, this review aims to demonstrate the impact of C. elegans models on the drug discovery pipeline.Fil: Giunti, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Andersen, Natalia Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Rayes, Diego Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: de Rosa, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentin