Evaluation of immune responses to adeno-associated virus (AAV)-mediated gene therapies prior to and following dose administration plays a key role in determining therapeutic safety and efficacy. This ...report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec (BMN 270), an AAV5-mediated gene therapy encoding human B domain-deleted FVIII (hFVIII-SQ) in a phase 1/2 clinical study of adult males with severe hemophilia A. Patients with pre-existing humoral immunity to AAV5 or with a history of FVIII inhibitors were excluded from the trial. Blood plasma and peripheral blood mononuclear cell (PBMC) samples were collected at regular intervals following dose administration for assessment of humoral and cellular immune responses to both the AAV5 vector and transgene-expressed hFVIII-SQ. The predominant immune response elicited by BMN 270 administration was largely limited to the development of antibodies against the AAV5 capsid that were cross-reactive with other common AAV serotypes. No FVIII inhibitor responses were observed within 3 years following dose administration. In a context of prophylactic or on-demand corticosteroid immunosuppression given after vector infusion, AAV5 and hFVIII-SQ peptide-specific cellular immune responses were intermittently detected by an interferon (IFN)-γ and tumor necrosis factor (TNF)-α FluoroSpot assay, but they were not clearly associated with detrimental safety events or changes in efficacy measures.
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This report describes up to 3 years of immunogenicity data following administration of valoctocogene roxaparvovec, an AAV5-mediated gene therapy encoding hFVIII-SQ, in a phase 1/2 clinical study of adult males with severe hemophilia A. Immunogenicity elicited by BMN 270 administration was predominantly a humoral antibody response against the AAV5 capsid. No FVIII inhibitor responses were observed within 3 years following dose administration. No immunogenicity measures were consistently associated with detrimental safety or efficacy parameters.
The intelligent construction of non-noble metal materials that exhibit reversible oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) with bifunctional electrocatalytic performance is ...greatly coveted in the realm of zinc-air batteries (ZABs). Herein, a crafted structure-amorphous MnO
lamellae encapsulated covalent triazine polymer-derived N, S, P co-doped carbon sphere (A-MnO
/NSPC) is designed using a self-doped pyrolysis coupled with an in situ encapsulation strategy. The customized A-MnO
/NSPC-2 demonstrates a superior bifunctional electrocatalytic performance, confirmed by a small ΔE index of 0.64 V for ORR/OER. Experimental investigations, along with density functional theory calculations validate that predesigned amorphous MnO
surface defects and abundant heteroatom catalytic active sites collectively enhance the oxygen electrocatalytic performance. Impressively, the A-MnO
/NSPC-based rechargeable liquid ZABs show a large open-circuit potential of 1.54 V, an ultrahigh peak power density of 181 mW cm
, an enormous capacity of 816 mAh g
, and a remarkable stability for more than 1720 discharging/charging cycles. Additionally, the assembled flexible all-solid-state ZABs also demonstrate outstanding cycle stability, surpassing 140 discharging/charging cycles. Therefore, this highly operable synthetic strategy offers substantial understanding in the development of magnificent bifunctional electrocatalysts for various sustainable energy conversions and beyond.
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity ...against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (
= 56), 46.2% in Russia (
= 91), 40% in Italy (
= 20), 37.2% in France (
= 86), 26.8% in the United States (
= 71), 26.9% in Brazil (
= 26), 28.1% in Germany (
= 89), 29.8% in Japan (
= 84), and 5.9% in the United Kingdom (
= 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
This paper proposes the design of video image hardware structure processing based on FPGA. This improves the processing speed and real-time performance of the intelligent automatic assembly pipeline ...inspection system. The system uses background difference method to detect moving targets. The static scene in the image is eliminated by binarization method. Morphological filtering is then done to eliminate voids and noise points. Finally, the target center point is extracted. Adopt modular design and pipeline processing mode. The high-speed parallel processing of FPGA and large capacity of DDR2SDRAM are fully utilized. A standard equipment for epitope error consistency and a fault simulator are designed. The control software for the test system is developed. The analysis model of calibration data is established. The measurement uncertainty analysis process of test results is given based on GUM algorithm. Practice test results show that the system can effectively detect moving objects.
•The direct-seeding path for rice covers the entire field.•Rice direct-seeding path includes the encircling path around the field blocks.•Encircling path planning algorithm is applicable to different ...shapes fields.•The path planning encompasses various patterns and path sequences.
Path planning is one of the key technologies that determines the efficiency and quality of field operations using autonomous agricultural machinery. To date, there has been extensive research on global coverage path planning for unmanned agricultural machinery within the working area; however, the issue of “encircling and edging” left by the machinery during headland turns is often overlooked. This study focuses on the operational conditions of unmanned agricultural machinery in the rice fields of southern China. The path planning problem is abstracted under physical constraints, such as the space at the field headland, the agricultural environment (e.g., types of field ridges), the turning characteristics of the machinery, turning radius, working width, and minimum safety distance, into mathematical constraints. This yields an optimized path planning model and sequence combination. Based on the improved Reeds–Shepp curve, an en-circling and edging path planning algorithm is designed. The planned path for the unmanned agricultural machinery from start to finish consists only of arcs and straight lines, suitable for the right-angle turning, reversing, and 180° U-turn operations required for rice field machinery, thus significantly improving the coverage of field edges and missed areas at the headland. A rice direct-seeding machine was used as a test subject for encircling and edging field trials, with tests conducted in rectangular, trapezoidal, and irregular quadrilateral rice fields. The results show that, for rectangular plots, the full-field coverage rate of rice direct-seeding operations can reach 96.44%; for trapezoidal plots, the coverage rate is 95.47%; and for irregular quadrilateral fields, the coverage rate is 95.69%. These results are promising, indicating that the encircling and edging path planning based on the improved Reeds–Shepp curve can effectively increase the full-field coverage rate of unmanned agricultural machinery, improving work quality and meeting the needs of modernized, intelligent agricultural machinery operations.
Phenylketonuria (PKU) is characterized by a deficiency in phenylalanine hydroxylase (PAH) that may lead to elevated blood phenylalanine (Phe) and significant neurocognitive and neuropsychological ...comorbidities. Pegvaliase (PALYNZIQ®, BioMarin Pharmaceutical Inc.) is a PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), which converts Phe to trans-cinnamic acid and ammonia, and was approved in May 2018 in the United States and in May 2019 in the European Union for decreasing blood Phe levels in adults with PKU with blood Phe levels >600 μmol/L. The efficacy and safety of pegvaliase was assessed in two phase 2 dose-finding studies in adults with PKU (PAL-002, NCT00925054, and PAL-004, NCT01212744). Participants completing these studies could enroll in a long-term extension study (PAL-003, NCT00924703).
Participants in PAL-002 received pegvaliase 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg weekly for 8 weeks, then continued treatment for a further 8 weeks with dose and/or frequency adjusted to achieve blood Phe concentrations of 60 to 600 μmol/L. Participants in PAL-004 received pegvaliase 0.001 to 0.4 mg/kg 5 days/week for 13 weeks, with modifications made to the starting dose in response to safety and/or efficacy, followed by 3 additional weeks of follow-up assessments. The maximum allowable daily dose in both studies was 1.0 mg/kg/day (5.0 mg/kg/week). Participants who completed any of the phase 2 studies (PAL-002; PAL-004; or a third phase 2 study, 165-205) were eligible to enroll in an open-label, multicenter, long-term extension study (PAL-003, NCT00924703).
Thirty-seven of the 40 enrolled participants completed PAL-002 and 15 of the 16 enrolled participants completed PAL-004. Mean blood Phe at baseline was 1311.0 (standard deviation SD 354) μmol/L in PAL-002 and 1482.1 (SD 363.5) μmol/L in PAL-004. Mean blood Phe did not substantially decrease with pegvaliase treatment in PAL-002 (−206.3 SD 287.1 μmol/L at Week 16) or PAL-004 (−410.8 SD 653.7 μmol/L at Week 13). In PAL-004, mean blood Phe dropped from baseline by 929.1 μmol/L (SD 691.1) by Week 2; subsequent to dose modifications and interruptions, this early decrease in mean Phe level was not sustained. With increased pegvaliase dose and duration in PAL-003, mean blood Phe levels steadily decreased from baseline, with mean reductions by Week 120 of 68.8% (SD 44.2%) in PAL-002 participants and 75.9% (SD 32.4%) in PAL-004 participants. All participants in PAL-002 and PAL-004 reported ≥1 adverse event (AE), with higher exposure-adjusted event rates in PAL-004. The majority of AEs were mild (87.2% in PAL-002, 86.7% in PAL-004) or moderate (12.4% in PAL-002, 13.3% in PAL-004). The most commonly reported AEs in PAL-002 were injection site reaction (50.0% of participants), headache (42.1%), injection site erythema (36.8%), nausea (34.2%), and arthralgia (29.0%), and in PAL-004 were arthralgia (75.0%), headache (62.5%), dizziness (56.3%), injection site erythema (56.3%), and injection site reaction (50.0%).
In two phase 2 dose-finding studies, pegvaliase did not lead to substantial blood Phe reductions. Higher and more frequent pegvaliase dosing in PAL-004 led to a substantial initial drop in blood Phe, but an increase in the number of hypersensitivity AEs and dose reductions or interruptions. With increased dose and duration of treatment in PAL-003, mean blood Phe reduction was substantial and sustained, and the frequency of hypersensitivity AEs decreased and stabilized. Together, these studies led to the development of an induction-titration-maintenance regimen that has been approved for pegvaliase, with patients starting at a low weekly dose that gradually increases in dose and frequency until they achieve a standard non-weight-based daily maintenance dose. This regimen has been tested in a third phase 2 study, as well as in two successful phase 3 studies of pegvaliase.
Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are ...associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU.
Pegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Phe ≤ 600 μmol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Phe ≤ 600 μmol/L for at least 4 weeks without dose modification. Analyses were performed for participants who achieved (Group A, n = 11) and did not achieve (Group B, n = 13) maintenance dose during the first 24 weeks of study treatment.
Baseline mean blood Phe for Group A and Group B were 1135 μmol/L and 1198 μmol/L, respectively. Mean blood Phe ≤ 600 μmol/L was achieved for Group A by Week 11 (mean blood Phe of 508 ± 483 μmol/L) and for Group B by Week 48 (mean blood Phe of 557 ± 389 μmol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B.
Pegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.
A low-cost, low-crosstalk, and full-resolution autostereoscopic three-dimensional (3D) display system is described in this paper. The vivid 3D image is realized with the crosstalk below 10%. The full ...resolution of the display panel is retained by displaying left and right images sequentially and switching the light emitting diode (LED) directional backlight in synchronism with this. An eye position tracker is used to control the output of the LEDs with a liquid crystal spatial light modulator (SLM) so that the left and right exit pupils formed are located at the user's left and right eyes. The depth of this system is less than 20 cm and the cost are considerably lower than commercial 3D display systems, which makes it suitable for domestic desktop 3D display applications.
Introduction
Valoctocogene roxaparvovec uses an adeno‐associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing ...bleeding protection.
Aim
To assess safety and efficacy of valoctocogene roxaparvovec 5‒6 years post‐treatment.
Methods
In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti‐AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 1013 vg/kg; n = 7) and 5 (4 × 1013 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported.
Results
No new treatment‐related safety signals emerged. During year 6, a participant in the 6 × 1013 vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25 × 10−5 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration‐containing cells occurred. During all follow‐ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, representing proportionally smaller year‐over‐year declines than earlier timepoints.
Conclusions
Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.
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