Search

Your search keyword '"Scott P. Henry"' showing total 5 results
Start Over Author "Scott P. Henry" Publication Year Range Last 3 years
5 results on '"Scott P. Henry"'

1. Correlations between preclinical BJAB assay ranking of antisense drugs and clinical trial adverse events

Author

Wesley Partridge, Sebastien A. Burel, Annie Ferng, Shuting Xia, T. Jesse Kwoh, Scott P. Henry, and Brenda F. Baker

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Abstract This analysis sought to assess the clinical predictivity of an in vitro assay which utilized the human B‐lymphoma BJAB cell line, for identification of antisense oligonucleotides (ASOs) with the potential to elicit innate immune activation in humans. Adverse events (AEs) from clinical trial data were analyzed based on prior clinical knowledge and network analysis of the clinical data to identify correlations with the BJAB assay. Clinically evaluated ASOs were ranked by the BJAB assay's mean log‐fold increase in TNF expression levels. Flu‐like reactions (FLRs) and injection site reactions (ISRs), were chosen as AEs of interest, along with those Medical Dictionary for Regulatory Activities preferred terms identified using AE network analysis. Fifteen different 2'‐O‐methoxyethyl (2'MOE) modified ASOs were ranked by the incidence of each AE group in the integrated safety data from 35 clinical trials. ISRs are considered to be local to the injection site, whereas FLRs are reflected by systemic constitutional symptoms. The correlations identified in this analysis of integrated clinical data provide evidence that the ASO sequences selected by the BJAB assay have a lower likelihood of causing systemic inflammatory AEs associated with FLRs, but not ISRs.

Published
2023
Full Text
View/download PDF

3. Inflammatory Non-CpG Antisense Oligonucleotides Are Signaling Through TLR9 in Human Burkitt Lymphoma B Bjab Cells

Author

Adam J. Pollak, Patrick Cauntay, Todd Machemer, Suzanne Paz, Sagar Damle, Scott P. Henry, and Sebastien A. Burel

Subjects
Toll-Like Receptor 9, Drug Discovery, Genetics, Leukocytes, Mononuclear, Molecular Medicine, Humans, Oligonucleotides, Antisense, Molecular Biology, Biochemistry, Burkitt Lymphoma
Abstract

Nucleic acid-based phosphorothioate containing antisense oligonucleotides (PS-ASOs) have the potential to activate cellular innate immune responses, and the level of activation can vary quite dramatically with sequence. Minimizing the degree of proinflammatory effect is one of the main selection criteria for compounds intended to move into clinical trials. While a recently developed human peripheral blood mononuclear cell (hPBMC)-based assay showed excellent ability to detect innate immune active PS-ASOs, which can then be discarded from the developmental process, this assay is highly resource intensive and easily affected by subject variability. This compelled us to develop a more convenient high-throughput assay. In this study, we describe a new

Published
2022

4. Early-Stage Identification and Avoidance of Antisense Oligonucleotides Causing Species-Specific Inflammatory Responses in Human Volunteer Peripheral Blood Mononuclear Cells

Author

Sebastien A. Burel, Todd Machemer, Brenda F. Baker, T. Jesse Kwoh, Suzanne Paz, Husam Younis, and Scott P. Henry

Subjects
Interleukin-6, Drug Discovery, Genetics, Leukocytes, Mononuclear, Molecular Medicine, Humans, Oligonucleotides, Antisense, Molecular Biology, Biochemistry, Healthy Volunteers
Abstract

A human peripheral blood mononuclear cell (PBMC)-based assay was developed to identify antisense oligonucleotide (ASO) with the potential to activate a cellular innate immune response outside of an acceptable level. The development of this assay was initiated when ISIS 353512 targeting the messenger ribonucleic acid for human C-reactive protein (CRP) was tested in a phase I clinical trial, in which healthy human volunteers unexpectedly experienced increases in interleukin-6 (IL-6) and CRP. This level of immune stimulation was not anticipated following rodent and nonhuman primate safety studies in which no evidence of exaggerated proinflammatory effects were observed. The IL-6 increase induced by ISIS 353512 was caused by activation of B cells. The IL-6 induction was inhibited by chloroquine pretreatment of PBMCs and the nature of ASOs suggested that the response is mediated by a Toll-like receptor (TLR), in all likelihood TLR9. While assessing the inter PBMC donor variability, two classes of human PBMC responders to ISIS 353512 were identified (discriminator and nondiscriminators). The discriminator donor PBMCs were shown to produce low level of IL-6 after 24 h in culture, in the absence of ASO treatment. The PBMC assay using discriminator donors was shown to be reproducible, allowing to assess reliably the immune potential of ASOs by comparison to known benchmark ASO controls that were previously shown to be either safe or inflammatory in clinical trials. Clinical Trial registration numbers: NCT00048321 NCT00330330 NCT00519727.

Published
2022

5. Evaluation of flaw detection algorithm using simulated X-ray computed tomography of ground truth data

Author

Kim, Felix H, Pintar, Adam L, Scott, John Henry J., and Garboczi, Edward J

Abstract

A framework to generate simulated X-ray computed tomography (XCT) data of ground truth (denoted here as ‘GT’) flaws was developed for evaluation of flaw detection algorithms using image comparison metrics. The flaws are mimicking some of those found in additively manufactured parts. The simulated flaw structure gives a GT data set with which to quantitatively evaluate, by calculating exact errors, the results of flaw detection algorithms applied to simulated XCT images. The simulated data avoid time-consuming manual voxel labeling steps needed for many physical data sets to generate GT images. The voxelated pore meshes that exactly match GT images avoid approximations due to converting continuum pore meshes to voxelated GT images. Spherical pores of varying sizes were randomly distributed near the surface and interior of a cylindrical part. XCT simulation was carried out on the structure at three different signal-to-noise levels by changing the number of frames integrated for each projection. Two different local thresholding algorithms (a commercial code and the Bernsen method) and a global thresholding algorithm (Otsu) were used to segment images using varying sets of algorithm parameters. The segmentation results were evaluated with various image evaluation metrics, which showed different behaviors for the three algorithms regarding “closeness” to the GT data. An approach to optimize the thresholding parameters is demonstrated for the commercial flaw detection algorithm based on the semantic evaluation metrics. A framework to evaluate pore sizing error and binary probability of detection was further demonstrated to compare the optimization results.

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results