Science with the Einstein Telescope: a comparison of different designs

The Einstein Telescope (ET), the European project for a third-generation gravitational-wave detector, has a reference configuration based on a triangular shape consisting of three nested detectors with 10 km arms, where in each arm there is a `xylophone' configuration made of an interferometer tuned toward high frequencies, and an interferometer tuned toward low frequencies and working at cryogenic temperature. Here, we examine the scientific perspectives under possible variations of this reference design. We perform a detailed evaluation of the science case for a single triangular geometry observatory, and we compare it with the results obtained for a network of two L-shaped detectors (either parallel or misaligned) located in Europe, considering different choices of arm-length for both the triangle and the 2L geometries. We also study how the science output changes in the absence of the low-frequency instrument, both for the triangle and the 2L configurations. We examine a broad class of simple `metrics' that quantify the science output, related to compact binary coalescences, multi-messenger astronomy and stochastic backgrounds, and we then examine the impact of different detector designs on a more specific set of scientific objectives.Comment: 197 pages, 72 figure

Safe and Sustained Expression of Human Iduronidase After Intrathecal Administration of Adeno-Associated Virus Serotype 9 in Infant Rhesus Monkeys

Many neuropathic diseases cause early, irreversible neurologic deterioration, which warrants therapeutic intervention during the first months of life. In the case of mucopolysaccharidosis type I, a recessive lysosomal storage disorder that results from a deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), one of the most promising treatment approaches is to restore enzyme expression through gene therapy. Specifically, administering pantropic adeno-associated virus (AAV) encoding IDUA into the cerebrospinal fluid (CSF) via suboccipital administration has demonstrated remarkable efficacy in large animals. Preclinical safety studies conducted in adult nonhuman primates supported a positive risk-benefit profile of the procedure while highlighting potential subclinical toxicity to primary sensory neurons located in the dorsal root ganglia (DRG). This study investigated the long-term performance of intrathecal cervical AAV serotype 9 gene transfer of human IDUA administered to 1-month-old rhesus monkeys (N = 4) with half of the animals tolerized to the human transgene at birth via systemic administration of an AAV serotype 8 vector expressing human IDUA from the liver. Sustained expression of the transgene for almost 4 years is reported in all animals. Transduced cells were primarily pyramidal neurons in the cortex and hippocampus, Purkinje cells in the cerebellum, lower motor neurons, and DRG neurons. Both tolerized and non-tolerized animals were robust and maintained transgene expression as measured by immunohistochemical analysis of brain tissue. However, the presence of antibodies in the non-tolerized animals led to a loss of measurable levels of secreted enzyme in the CSF. These results support the safety and efficiency of treating neonatal rhesus monkeys with AAV serotype 9 gene therapy delivered into the CSF

Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates

The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy

HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo.

We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts

Animal Characteristics, Drug Treatment Study.^A

A<p>Sedated with 0.1 cc/kg 10% Ketamine IM.</p>B<p>Prior infection with <i>P. cynomolgi</i>. All others were previously infected with <i>P. knowlesi</i>.</p

Schematic for Drug Treatment Study.

<p>Based on our available pharmacokinetic data and based on the assumption that 4–5 times half-life is required to reach steady state and then to eliminate drug in plasma <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100138#pone.0100138-Birkett1" target="_blank">[14]</a>, drugs levels were assumed to be at steady state (with dosing starting at D −2, and continued through D4) and mostly eliminated by the end of <i>P. knowlesi</i> liver stages (last dose given at 32 hr, and liver stages last about 5.25 days, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100138#pone.0100138-Coatney1" target="_blank">[9]</a>). On D −2, animals were infected IV with 2,500 cryopreserved <i>P. knowlesi</i> sporozoites. Smears and dried blood spots for PCR were collected every day from D5–14 and every other day from D14–D28. Animals were treated if parasites were detected on smear or on D28 (end of study) if smear negative throughout the study.</p

Pharmacokinetics of Lopinavir-ritonavir in Rhesus Monkeys.

A<p>Sedated with 0.1 cc/kg 10% Ketamine IM.</p>B<p>Awake.</p>1<p>Ibarra M, Fagiolino P, Vázquez M, Ruiz S, Vega M, Bellocq B, Pérez M, González B, Goyret A. Impact of food administration on lopinavir-ritonavir bioequivalence studies. Eur J Pharm Sci. 2012 Aug 15;46(5):516–21.</p

Trimethoprim-Sulfamethoxazole, and Lopinavir-ritonavir when used with Trimethoprim-Sulfamethoxazole, but not Lopinavir-ritonavir alone, at clinically relevant concentrations inhibits <i>P. knowlesi</i> liver stage parasites as reflected in absence of parasites in the blood by smear for 28 days (A) and prolonged time to PCR detection (B).

<p>To ensure drug steady state drug and 100% infection, rhesus (<i>Macaca mulatta</i>) monkeys were dosed starting 2 days prior to (D −2) through D4 post infection (with infection defined as D0) with 2,500 purified, cryopreserved <i>P. knowlesi</i> H strain sporozoites IV. Pharmacokinetic modeling used in this experiment predicted all drugs would be reduced to non-active levels prior to parasite emergence from the liver. Animals had Giemsa-stained smear and blood obtained from ear pricks until D28. Prolonged time to detection of parasites in blood was used to gauge liver stage parasite killing. (A) Control- and LPV-RTV-treated animals had positive smears on D10 and 11, and D10 and 12, respectively, but animals treated with TMP-SMX or LPV-RTV+TMP-SMX never became blood smear positive through D28, suggesting reduction of liver stage parasite burden. These findings were confirmed using (B) PCR for detection of parasites in blood (sensitivity, 0.00019 parasites/µl): parasites were detected earlier by PCR on D6 and 7 in controls and LPV-RTV (only)-treated animals, but on D12 in TMP-SMX only or in LPV-RTV+TMP-SMX combination-treated animals. Thus, LPV-RTV had no effect on the time to detection of parasites in blood, but TMP-SMX and LPV-RTV+TMP-SMX-treated animals had significant delays in detection of parasites in the blood, reflecting a reduced liver stage parasite burden.</p