Biology subjects

Baker, S. W.

Publications and source records attributed to Baker, S. W..

8 recordsLinked to original sources

bioRxiv2023

Sustained Delivery of GLP-1 Receptor Agonists from Injectable Biomimetic Hydrogels Improves Treatment of Diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone and neurotransmitter secreted from intestinal L-cells in response to nutrients to stimulate insulin and block glucagon secretion in a glucose-dependent manner. GLP-1 in itself is rapidly degraded, but long-acting GLP-1 receptor agonists (GLP-1 RAs) have become central in the treatment of T2D because of the beneficial effects extending also beyond glucose control. Currently, these therapeutics must be injected either daily or weekly or taken daily orally, leaving room for technological innovations that enable less frequent administrations, which will reduce patient burden and increase patient compliance. An ideal GLP-1 RA drug product would provide continuous therapy for upwards of four months from a single administration to match the cadence with which T2D patients typically visit their physician. In this work, we leveraged an injectable hydrogel depot technology to develop a long-acting GLP-1 RA drug product. By modulating the hydrogel properties to tune GLP-1 RA retention within the hydrogel depot, we engineered formulations capable of months-long GLP-1 RA delivery. Using a rat model of T2D, we confirmed that a single injection of hydrogel-based therapies exhibits sustained exposure of GLP-1 RA over 42 days, corresponding to a once-every four month therapy in humans. Moreover, these hydrogel therapies maintained optimal management of blood glucose and weight comparable to daily injections of a leading GLP-1 RA drug molecule. The pharmacokinetics and pharmacodynamics of these hydrogel-based long-acting GLP-1 RA treatments are promising for development of novel therapies reducing treatment burden for more effective management of T2D. Progress and PotentialWhile insufficient access to quality healthcare is problematic for consistent management of Type II diabetes (T2D), poor adherence to burdensome treatment regimens is one of the greatest challenges for disease management. Glucagon-like peptide 1 (GLP1) drugs have become central to the treatment of T2D due to their many beneficial effects beyond improving glucose control. Unfortunately, while optimization of GLP1 drugs has reduced treatment frequency from daily to weekly, significant patient burden still leads to poor patience compliance. In this work we developed an injectable hydrogel technology to enable GLP1 drugs only requiring administration once every four months. We showed in a rat model of T2D that one injection of a hydrogel-based therapy improves management of blood glucose and weight when compared with daily injections of the leading drug used clinically. These hydrogel-based GLP1 treatments are promising for reducing treatment burden and more effectively managing T2D. Future ImpactA GLP-1-based drug product providing four months of continuous therapy per administration could be transformational for the management of Type II diabetes (T2D). One of the most challenging aspects of diabetes management with GLP-1 mimics is maintenance of consistent levels of the drugs in the body, which is complicated by poor patient compliance on account of the high frequency of dosing required for current treatments. By leveraging a unique sustained release hydrogel depot technology we develop a months-long GLP-1 drug product candidate that has the potential to reduce patient burden and improving diabetes management. Overall, the hydrogel technology we describe here can dramatically reduce the frequency of therapeutic interventions, significantly increasing patient quality of life and reducing complications of diabetes management. Our next steps will focus on optimization of the drug formulations in a swine model of T2D, which is the most advanced and translationally-relevant animal model for these types of therapeutics. The long-term vision for this work is to translate lead candidate drug products towards clinical evaluation, which will also require comprehensive safety evaluation in multiple species and manufacturing our these materials according to Good Manufacturing Practices. The months-long-acting GLP-1 drug product that will come from this work has the potential to afford thus far unrealized therapeutic impact for the hundreds of millions of people with diabetes worldwide.

bioengineering↗

bioRxiv2021

Capacity to erase gene occlusion is a defining feature distinguishing naive from primed pluripotency

Pluripotent stem cells can exist in either the naive state representing a developmental blank slate or the downstream primed state poised for differentiation. Currently, known differences between these two states are mostly phenomenological, and none can adequately explain why the two states should differ in developmental priming. Gene occlusion is a mode of epigenetic inactivation that renders genes unresponsive to their cognate transcriptional activators. It plays a crucial role in lineage restriction. Here, we report that a defining feature distinguishing the two pluripotent states lies in the ability of naive but not primed cells to erase occlusion. This "deocclusion" capacity requires Esrrb, a gene expressed only in the naive but not primed state. Notably, Esrrb silencing in the primed state is itself due to occlusion. Collectively, our data argue that the Esrrb-dependent deocclusion capacity in naive cells is key for sustaining naive pluripotency, and the loss of this capacity in the primed state via the occlusion of Esrrb poises cells for differentiation.

molecular biology↗

bioRxiv2020

CBX1 mutations cause a neurodevelopmental syndrome due to heterochromatin organizational alterations

PurposeThis study aimed to establish variants in CBX1, encoding heterochromatin protein 1{beta} (HP1{beta}), as a cause of a novel syndromic neurodevelopmental disorder. MethodsPatients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays, neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. ResultsIn three unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1 {beta}, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1{beta} binding to heterochromatin, while HP1{beta} interactome analysis demonstrated that the majority of HP1{beta}-interacting proteins remained unchanged between the wild-type and mutant HP1{beta}. ConclusionThese collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1{beta} chromatin binding during neurocognitive development. As HP1{beta} forms homodimers and heterodimers, mutant HP1{beta} likely sequesters wild-type HP1{beta} and other HP1 proteins, exerting dominant-negative effects.

genetics↗

bioRxiv2020

Bibliome Variant Database: Automated Identification and Annotation of Genetic Variants in Primary Literature

The Bibliome Variant Database (BVdb) is a freely available reference database containing over 1 million human genetic variants mapped to the human genome that have been mined from primary literature. The BVdb is designed to facilitate variant interpretation in clinical and research contexts by reducing or eliminating the time required to search for literature describing a given variant. Users can search the database using gene symbols, HGVS variant nomenclature, genomic positions, or rsIDs. Each variant page lists references in the database that describe the variant, as well as the exact gene symbol and variant text description identified in each reference. AVAILABILITY AND IMPLEMENTATIONThe BVdb is freely available at http://bibliome.ai

bioinformatics↗

bioRxiv2020

Combinatorial Polyacrylamide Hydrogels for Preventing Biofouling on Implantable Biosensors

Biofouling on the surface of implanted medical devices severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers are currently considered "gold standard" device coatings to reduce biofouling. To discover novel anti-biofouling materials, we created a combinatorial library of polyacrylamide-based copolymer hydrogels and screened their ability to prevent fouling from serum and platelet-rich plasma in a high-throughput parallel assay. We found certain non-intuitive copolymer compositions exhibit superior antibiofouling properties over current gold standard materials, and employed machine learning to identify key molecular features underpinning their performance. For validation, we coated the surfaces of electrochemical biosensors with our hydrogels and evaluated their anti-biofouling performance in vitro and in vivo in rodent models. Our copolymer hydrogels preserved device function and enabled continuous measurements of a small-molecule drug in vivo better than gold standard coatings. The novel methodology we describe enables the discovery of anti-biofouling materials that can extend the lifetime of real-time in vivo sensing devices.

bioengineering↗

bioRxiv2020

Pattern Separation Contributes to Categorical Face Perception

Traditionally considered a memory structure, the hippocampus has been shown to contribute to non-memory functions, from perception to language. Recent evidence suggests that the ability to differentiate highly confusable faces could involve pattern separation, a mnemonic process mediated by the hippocampal dentate gyrus (DG). Hippocampal involvement, however, may depend on existing face memories. To investigate these possibilities, we tested BL, a rare individual with bilateral lesions selective to the DG, and healthy controls. Both were administered morphed images of famous and nonfamous faces in a categorical perception (CP) identification and discrimination experiment. All participants exhibited nonlinear identification of famous faces with a midpoint category boundary. Controls identified newly learned nonfamous faces with lesser fidelity, while BL showed a notable shift in category boundary. When discriminating face pairs, controls showed typical CP effects of better between-category than within-category discrimination -- but only for famous faces. BL showed extreme within-category "compression," reflecting his tendency to pattern complete following suboptimal pattern separation. We provide the first evidence that pattern separation contributes to CP of faces.

neuroscience↗

bioRxiv2018

Genetic And Epigenetic Fine Mapping Of Complex Trait Associated Loci In The Human Liver

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

genetics↗

bioRxiv2018

Rapid interpretation of clinical exomes using Phenoxome: a computational phenotype-driven approach

Clinical exome sequencing (CES) has become the preferred diagnostic platform for complex pediatric disorders with suspected monogenic etiologies, solving up to 20%-50% of cases depending on indication. Despite rapid advancements in CES analysis, the major challenge still resides in identifying the casual variants among the thousands of variants detected during CES testing, and thus establishing a molecular diagnosis. To improve the clinical exome diagnostic efficiency, we developed Phenoxome, a robust phenotype-driven model that adopts a network-based approach to facilitate automated variant prioritization and subsequent classification. Phenoxome dissects the phenotypic manifestation of a patient in conjunction with their genomic profile to filter and then prioritize putative pathogenic variants. To validate our method, we have compiled a clinical cohort of 105 positive patient samples (i.e. at least one reported pathogenic variant) that represent a wide range of genetic heterogeneity from The Childrens Hospital of Philadelphia. Our approach identifies the causative variants within the top 5, 10, or 25 candidates in more than 50%, 71%, or 88% of these patient samples respectively. Furthermore, we show that our method is optimized for clinical testing by yielding superior ranking of the pathogenic variants compared to current state-of-art methods. The web application of Phenoxome is available to the public at http://phenoxome.chop.edu/.

bioinformatics↗