We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air–liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and ‘benchmarked’ against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90–100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotyped lentiviral vector into a first-in-man CF trial in 2017.

We present 594 radial velocity measurements for 71 white dwarfs obtained during our search for binary white dwarfs and not reported elsewhere. We identify three excellent candidate binaries, which require further observations to confirm our preliminary estimates for their orbital periods, and one other good candidate. We investigate whether our data support the existence of a population of single, low mass (<~0.5 solar masses) white dwarfs (LMWDs). These stars are difficult to explain in standard models of stellar evolution. We find that a model with a mixed single/binary population is at least ~20 times more likely to explain our data than a pure binary population. This result depends on assumed period distributions for binary LMWDs, assumed companion masses and several other factors. Therefore, the evidence in favour of the existence of a population of single LMWDs is not sufficient, in our opinion, to firmly establish the existence of such a population, but does suggest that extended observations of LMWDs to obtain a more convincing result would be worthwhile .Comment: 14 pages, 4 Figures. Accepted for publication in MNRAS. Added Institutio

We have discovered that the detached double degenerate binary WD 0957-666 has an orbital period of 1.46 hours, rather than the 1.15 day orbital period reported earlier. This is the shortest period example of such a system yet discovered. We obtain a unique period, which fits both our and earlier data. At this period the emission of gravitational radiation will cause the binary to merge within approximately 2.0 x 10 8 years. This system represents a population of short orbital period binaries which will merge within a Hubble time, and so could account for type Ia supernovae, although due to the low mass of both stars (0.3 to 0.4 M ⊙ ), it is unlikely to become a supernova itself. We have detected the companion star and have measured a mass ratio of q = 1.15±0.10. This is the third double degenerate for which q has been measured and all three have q ≃ 1, which is in conflict with the predicted mass ratio distribution which peaks at 0.7. This system is viewed close to edge on, and we estimate that the probability of this system undergoing eclipses is 15 %.

Double white dwarf (DWD) binaries are expected to be very common in the Milky Way, but their intrinsic faintness challenges the detection of these systems. Currently, only a few tens of detached DWDs are know. Such systems offer the best chance of extracting the physical properties that would allow us to address a wealth of outstanding questions ranging from the nature of white dwarfs, over stellar and binary evolution to mapping the Galaxy. In this paper we explore the prospects for detections of ultra-compact (with binary separations of a few solar radii or less) detached DWDs in: 1) optical radiation with Gaia and the LSST and 2) gravitational wave radiation with LISA. We show that Gaia, LSST and LISA have the potential to detect respectively around a few hundreds, a thousand, and 25 thousand DWD systems. Moreover, Gaia and LSST data will extend by respectively a factor of two and seven the guaranteed sample of binaries detected in electromagnetic and gravitational wave radiation, opening the era of multi-messenger astronomy for these sources.