Vector integration and fate in the hemophilia dog liver multi-years following AAV-FVIII gene transfer

Gene therapy using adeno-associated viral (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multi-year transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous, and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was non-integrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency= 9.3e-4 sites/cell), with small numbers of non-random common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality

The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance

Plasma levels of von Willebrand factor (VWF) vary considerably in the general population and this variation has been linked to several genetic and environmental factors. Genetic factors include 2 common single nucleotide variants (SNVs) located in VWF, rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), although to date the mechanistic basis for their association with VWF level is unknown. Using genotypic/phenotypic information from a European healthy control population, in vitro analyses of recombinant VWF expressing both SNVs, and in vivo murine models, this study determined the precise nature of their association with VWF level and investigated the mechanism(s) involved. Possession of either SNV corresponded with a significant increase in plasma VWF in healthy controls (P G on VWF levels was also confirmed in vivo. This increase in VWF protein corresponded to an increase in VWF messenger RNA (mRNA) resulting, in part, from prolonged mRNA half-life. In addition, coinheritance of both SNVs was associated with a lower VWF propeptide-to-VWF antigen ratio in healthy controls (P < .05) and a longer VWF half-life in VWF knockout mice (P < .0001). Both SNVs therefore directly increase VWF plasma levels through a combined influence on VWF biosynthesis and clearance, and may have an impact on disease phenotype in both hemostatic and thrombotic disorders

Observation of Ξb0→Ξc+Ds−\Xi_b^0 \rightarrow \Xi_c^+ D_s^- and Ξb−→Ξc0Ds−\Xi_b^- \rightarrow \Xi_c^0 D_s^- decays

International audienceThe $\Xi_b^0 \rightarrow \Xi_c^+ D_s^-$ and $\Xi_b^- \rightarrow \Xi_c^0 D_s^-$ decays are observed for the first time using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=13\mathrm{TeV}$, corresponding to an integrated luminosity of $5.1\mathrm{fb}^{-1}$. The relative branching fractions times the beauty-baryon production cross-sections are measured to be \begin{align*} \mathcal{R}\left(\frac{\Xi_b^0}{\Lambda_b^0}\right) \equiv \frac{\sigma\left(\Xi_b^0\right)}{\sigma\left(\Lambda_b^0\right)} \times \frac{\mathcal{B}\left(\Xi_b^0 \rightarrow \Xi_c^+ D_s^-\right)}{\mathcal{B}\left(\Lambda_b^0 \rightarrow \Lambda_c^0 D_s^-\right)} =(15.8\pm1.1\pm0.6\pm7.7)\%, \mathcal{R}\left(\frac{\Xi_b^-}{\Lambda_b^0}\right) \equiv \frac{\sigma\left(\Xi_b^-\right)}{\sigma\left(\Lambda_b^0\right)} \times \frac{\mathcal{B}\left(\Xi_b^- \rightarrow \Xi_c^0 D_s^-\right)}{\mathcal{B}\left(\Lambda_b^0 \rightarrow \Lambda_c^0 D_s^-\right)} =(16.9\pm1.3\pm0.9\pm4.3)\%, \end{align*} where the first uncertainties are statistical, the second systematic, and the third due to the uncertainties on the branching fractions of relevant charm-baryon decays. The masses of $\Xi_b^0$ and $\Xi_b^-$ baryons are measured to be $m_{\Xi_b^0}=5791.12\pm0.60\pm0.45\pm0.24\mathrm{MeV}/c^2$ and $m_{\Xi_b^-}=5797.02\pm0.63\pm0.49\pm0.29\mathrm{MeV}/c^2$, where the uncertainties are statistical, systematic, and those due to charm-hadron masses, respectively

A measurement of ΔΓs\Delta \Gamma_{s}

Using a dataset corresponding to 9 fb$^{−1}$ of integrated luminosity collected with the LHCb detector between 2011 and 2018 in proton-proton collisions, the decay-time distributions of the decay modes ${B}_s^0\to J/{\psi \eta}^{\prime }$ and ${B}_s^0\to J/\psi {\pi}^{+}{\pi}^{-}$ are studied. The decay-width difference between the light and heavy mass eigenstates of the ${B}_s^0$ meson is measured to be ∆Γ$_{s}$ = 0.087 ± 0.012 ± 0.009 ps$^{−1}$, where the first uncertainty is statistical and the second systematic.[graphic not available: see fulltext]Using a dataset corresponding to $9~\mathrm{fb}^{-1}$ of integrated luminosity collected with the LHCb detector between 2011 and 2018 in proton-proton collisions, the decay-time distributions of the decay modes $B_s^0 \rightarrow J/\psi \eta'$ and $B_s^0 \rightarrow J/\psi \pi^{+} \pi^{-}$ are studied. The decay-width difference between the light and heavy mass eigenstates of the $B_s^0$ meson is measured to be $\Delta \Gamma_s = 0.087 \pm 0.012 \pm 0.009 \, \mathrm{ps}^{-1}$, where the first uncertainty is statistical and the second systematic

Observation of Ξb0→Ξc+Ds−\Xi_b^0 \rightarrow \Xi_c^+ D_s^- and Ξb−→Ξc0Ds−\Xi_b^- \rightarrow \Xi_c^0 D_s^- decays

International audienceThe $\Xi_b^0 \rightarrow \Xi_c^+ D_s^-$ and $\Xi_b^- \rightarrow \Xi_c^0 D_s^-$ decays are observed for the first time using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}=13\mathrm{TeV}$, corresponding to an integrated luminosity of $5.1\mathrm{fb}^{-1}$. The relative branching fractions times the beauty-baryon production cross-sections are measured to be \begin{align*} \mathcal{R}\left(\frac{\Xi_b^0}{\Lambda_b^0}\right) \equiv \frac{\sigma\left(\Xi_b^0\right)}{\sigma\left(\Lambda_b^0\right)} \times \frac{\mathcal{B}\left(\Xi_b^0 \rightarrow \Xi_c^+ D_s^-\right)}{\mathcal{B}\left(\Lambda_b^0 \rightarrow \Lambda_c^0 D_s^-\right)} =(15.8\pm1.1\pm0.6\pm7.7)\%, \mathcal{R}\left(\frac{\Xi_b^-}{\Lambda_b^0}\right) \equiv \frac{\sigma\left(\Xi_b^-\right)}{\sigma\left(\Lambda_b^0\right)} \times \frac{\mathcal{B}\left(\Xi_b^- \rightarrow \Xi_c^0 D_s^-\right)}{\mathcal{B}\left(\Lambda_b^0 \rightarrow \Lambda_c^0 D_s^-\right)} =(16.9\pm1.3\pm0.9\pm4.3)\%, \end{align*} where the first uncertainties are statistical, the second systematic, and the third due to the uncertainties on the branching fractions of relevant charm-baryon decays. The masses of $\Xi_b^0$ and $\Xi_b^-$ baryons are measured to be $m_{\Xi_b^0}=5791.12\pm0.60\pm0.45\pm0.24\mathrm{MeV}/c^2$ and $m_{\Xi_b^-}=5797.02\pm0.63\pm0.49\pm0.29\mathrm{MeV}/c^2$, where the uncertainties are statistical, systematic, and those due to charm-hadron masses, respectively

Observation of the decays B(s)0→Ds1(2536)∓K±B_{(s)}^{0}\to D_{s1}(2536)^{\mp}K^{\pm}

International audienceThis paper reports the observation of the decays $B_{(s)}^{0}\to D_{s1}(2536)^{\mp}K^{\pm}$ using proton-proton collision data collected by the LHCb experiment, corresponding to an integrated luminosity of $9\,\mathrm{fb}^{-1}$. The branching fractions of these decays are measured relative to the normalisation channel $B^{0}\to \overline{D}^{0}K^{+}K^{-}$. The $D_{s1}(2536)^{-}$ meson is reconstructed in the $\overline{D}^{*}(2007)^{0}K^{-}$ decay channel and the products of branching fractions are measured to be $$\mathcal{B}(B_{s}^{0}\to D_{s1}(2536)^{\mp}K^{\pm})\times\mathcal{B}(D_{s1}(2536)^{-}\to\overline{D}^{*}(2007)^{0}K^{-})=(2.49\pm0.11\pm0.12\pm0.25\pm0.06)\times 10^{-5},$$$$\mathcal{B}(B^{0}\to D_{s1}(2536)^{\mp}K^{\pm})\times\mathcal{B}(D_{s1}(2536)^{-}\to\overline{D}^{*}(2007)^{0}K^{-}) = (0.510\pm0.021\pm0.036\pm0.050)\times 10^{-5}.$$ The first uncertainty is statistical, the second systematic, and the third arises from the uncertainty of the branching fraction of the $B^{0}\to \overline{D}^{0}K^{+}K^{-}$ normalisation channel. The last uncertainty in the $B_{s}^{0}$ result is due to the limited knowledge of the fragmentation fraction ratio, $f_{s}/f_{d}$. The significance for the $B_{s}^{0}$ and $B^{0}$ signals is larger than $10\,\sigma$. The ratio of the helicity amplitudes which governs the angular distribution of the $D_{s1}(2536)^{-}\to\overline{D}^{*}(2007)^{0}K^{-}$ decay is determined from the data. The ratio of the $S$- and $D$-wave amplitudes is found to be $1.11\pm0.15\pm 0.06$ and its phase $0.70\pm0.09\pm 0.04$ rad, where the first uncertainty is statistical and the second systematic

Measurement of J/ψJ/\psi-pair production in pppp collisions at s=13\sqrt{s}=13 TeV and study of gluon transverse-momentum dependent PDFs

International audienceThe production cross-section of $J/\psi$ pairs in proton-proton collisions at a centre-of-mass energy of $\sqrt{s}=13$ TeV is measured using a data sample corresponding to an integrated luminosity of 4.2 fb$^{-1}$ collected by the LHCb experiment. The measurement is performed with both $J/\psi$ mesons in the transverse momentum range $0<p_{\text{T}}<14$ GeV/$c$ and rapidity range $2.0<y<4.5$. The cross-section of this process is measured to be 16.36$\pm$0.28(stat)$\pm$0.88(syst) nb. The contributions from single-parton scattering and double-parton scattering are separated based on the dependence of the cross-section on the absolute rapidity difference $\Delta y$ between the two $J/\psi$ mesons. The effective cross-section of double-parton scattering is measured to be $\sigma_{\text{eff}}=$13.1$\pm$1.8(stat)$\pm$2.3(syst) mb. The distribution of the azimuthal angle $\phi_{\text{CS}}$ of one of the $J/\psi$ mesons in the Collins-Soper frame and the $p_{\text{T}}$-spectrum of the $J/\psi$ pairs are also measured for the study of the gluon transverse-momentum dependent distributions inside protons. The extracted values of $\langle\cos2\phi_{\text{CS}}\rangle$ and $\langle\cos4\phi_{\text{CS}}\rangle$ are consistent with zero, but the presence of azimuthal asymmetry at a few percent level is allowed