Biology subjects

Hickey, E.

Publications and source records attributed to Hickey, E..

5 recordsLinked to original sources

bioRxiv2026

Patient-Centric Development of a Low-Volume, Low-Viscosity, Once Every 4 Weeks (Q4W) Autoinjector Combination Product for Povetacicept

Biologic therapies delivered subcutaneously (SC) are increasingly moving toward at-home self-administration using drug-device combination products. This shift places greater emphasis on the patient experience, and factors such as dose volume, injection time, dosing frequency, viscosity, injection force, and ease of use can affect treatment burden. This article focuses on the impact of balancing high protein concentration with low viscosity during drug product formulation development for an improved patient experience for povetacicept, an investigational, subcutaneously administered dual B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) inhibitor being developed for the treatment of multiple kidney diseases, including IgA nephropathy (IgAN). For povetacicept, formulation and device considerations were integrated throughout development. Studies evaluated protein concentration, dose volume, viscosity, injection force, injection time, and usability, in addition to standard stability, to develop a low-volume Q4W autoinjector. The selected 175 mg/mL formulation delivers an 80 mg dose in 0.46 mL. The viscosity was no more than 10 cP at 15-25{degrees}C and in a 1 mL prefilled syringe, the average glide force was 6 N, and the injection time at a constant force of 20 N was < 2 seconds. The same prefilled syringe was incorporated into an autoinjector with an injection time of less than 2 seconds in air. We conducted a limited assessment of an approved treatment for IgAN (Voyxact) administered via prefilled syringe (PFS) for effects of viscosity, fill volume and syringe configuration under the same experimental conditions. The viscosity at room temperature was 16 cP, with an average glide force of 27N and injection time of 19 seconds for the 2 mL dose. In conclusion, povetacicept was designed to support convenient and user-friendly at-home self-administration through Q4W dosing, a low injection volume, a low viscosity formulation, rapid delivery, and an easy-to-use autoinjector. This integrated formulation and device development approach demonstrates how patient-centric considerations can be incorporated in combination product development. Together, these attributes have the potential to reduce the practical burden associated with repeated, long-term treatment for IgAN patients.

bioengineering↗

bioRxiv2025

Maternal type 2 immunity promotes a microchimeric transfer of systemic type 2 immunity to offspring.

During maternity mothers undergo an immune pivot to a type 2 immune phenotype which is independent of any antigen experience. In this study we present this maternal Type 2 immunity as a key enabler of optimal maternally-driven microchimeric transfer of immunity to helminth infection in offspring. To demonstrate that maternal type 2 immunity dictates offspring immunity we nursed wildtype (WT) offspring on WT or IL-4R-/- foster mothers. WT offspring nursed on IL-4Ra-/- mothers acquired a reduced type 2 immune signature compared to WT offspring nursed on WT mothers. This demonstrated maternal IL-4R imprints type 2 immunity in offspring. This increased type 2 immunity in offspring related to a maternal IL-4R dependent increased frequency of maternal microchimeric cells (MMc) being detected in offspring. Higher worm burdens were detected in offspring nursed on IL-4R-/- mothers, demonstrating that an antigen independent promotion of maternal type 2 immunity provides offspring with protective immunity against a helminth infection. To establish the contribution of increased MMc in offspring nursed on WT mothers in the control of infection, we undertook an antibody mediated depletion of MMc cells in WT offspring. This MMc depletion impaired the control of infection and reduced the magnitude of offspring type 2 immune response against a helminth infection. These findings present antigen independent maternal IL-4R driven type 2 immunity during pregnancy as critical for imparting a profound immune influence via MMc on offspring immunity to infection.

immunology↗

bioRxiv2024

Zebrafish and cellular models of SELENON-Related Myopathy exhibit novel embryonic and metabolic phenotypes

SELENON-Related Myopathy (SELENON-RM) is a rare congenital myopathy caused by mutations of the SELENON gene characterized by axial muscle weakness and progressive respiratory insufficiency. Muscle histopathology commonly includes multiminicores or a dystrophic pattern but is often non-specific. The SELENON gene encodes selenoprotein N (SelN), a selenocysteine-containing redox enzyme located in the endo/sarcoplasmic reticulum membrane where it colocalizes with mitochondria-associated membranes. However, the molecular mechanism(s) by which SelN deficiency causes SELENON-RM are undetermined. A hurdle is the lack of cellular and animal models that show assayable phenotypes. Here we report deep-phenotyping of SelN-deficient zebrafish and muscle cells. SelN-deficient zebrafish exhibit changes in embryonic muscle function and swimming activity in larvae. Analysis of single cell RNAseq data in a zebrafish embryo-atlas revealed coexpression between selenon and genes involved in glutathione redox pathway. SelN-deficient zebrafish and mouse myoblasts exhibit changes in glutathione and redox homeostasis, suggesting a direct relationship with SelN function. We report changes in metabolic function abnormalities in SelN-null myotubes when compared to WT. These results suggest that SelN has functional roles during zebrafish early development and myoblast metabolism.

molecular biology↗

bioRxiv2023

Single nucleus transcriptome of a "Super RV" shows increased insulin and angiogenesis signaling

The right ventricle (RV) is one of the four pumping chambers of the heart, pumping blood to the lungs. In severe forms of congenital heart disease and pulmonary hypertension, the RV is made to pump into the systemic circulation. Such systemic RVs typically display early failure due to pressure overload. In rare cases a systemic RV persists into later decades of life - colloquially called a Super RV. Here we present the single-nucleus transcriptome of a systemic RV from a 60-year-old with congenitally corrected transposition of great arteries (ccTGA). Our data shows two specific signaling pathways enriched in the ccTGA RV myocardium. First, we show increased insulin like growth factor (IGF1) signaling within the systemic RV myocardium: there is increased expression of the main receptor IGFR1 within the cardiomyocytes, and IGF1 ligands within the cardiofibroblasts and macrophages. Second, we find increased VEGF and Wnt9 ligand expression in cardiomyocytes and increased VEGF1R and Wnt9 receptors in endothelial cells, which are implicated in angiogenesis. We show that increased insulin and angiogenesis signaling are potentially beneficial RV adaptations to increased pressure overload. This study of an adult systemic RV provides an important framework for understanding RV remodeling to systemic pressures in congenital heart disease and pulmonary hypertension.

developmental biology↗

bioRxiv2019

Microbial Signalling of Rhizobium Bacteria as a Method for Cereal Crop Germination Enhancement

1.Rhizobium nitrogen-fixing bacteria are a well studied microorganism family in the scientific community and its effects have been investigated thoroughly since its initial identification. This study aimed to research further the interactions of this bacteria with members of non-legume plant families, i.e. the poaceae grass species. This multi-year experimental series focuses on the germination stage of these plants, with varying treatments being applied to the seeds pre-germination in order to first test for a quantifiable effect taking place, and later to characterise the mechanism due to which an effect was noted. The identifier used to establish the presence of an effect was the germination rate of the seeds, which was found by examining the testa of each seed for the emergence of a radicle or plumule. Approximately 15,000 samples were tested during this process, the results of which were subsequently statistically analysed at a 95% confidence level. A conclusive increase of 40% (p<0.0001) was noted in the germination of barley seeds when treated with R. leguminosarum. Following tests which confirmed increase enzymatic activity, tests using a different bacterium (A. tumefaciens) and further review of existing literature, it was deemed likely that this effect was due to the release of lipo-chitooligosaccharides (LCOs) by the bacteria. It has been established that synthetically isolated LCOs can positively effect barley germination. It is believed that this is the first time it has been demonstrated that free Rhizobium bacteria in suspension can stimulate faster germination in the poaceae species due to the natural release of LCOs by the bacteria.

plant biology↗