Biology subjects

Newell, R.

Publications and source records attributed to Newell, R..

3 recordsLinked to original sources

bioRxiv2024

A rational approach for the targeted discovery and characterisation of microbiome-derived therapeutics

The human gut microbiome is intrinsically involved in health and disease, representing a wealth of untapped therapeutic potential. Here, we demonstrate the utility and potential of a metagenome guided, large cohort-based approach for the rational selection of live biotherapeutics from the human gut. We applied this approach to Inflammatory Bowel Disease (IBD), identifying several lead candidates that were significantly depleted in individuals with IBD compared to healthy controls. Their therapeutic potential was assessed in preclinical models of IBD where they improved markers of disease pathology by reducing inflammation and promoting mucosal healing and wound repair. All leads had excellent safety profiles in silico and in vitro, and several additionally presented favourable manufacturing properties, supporting their progression into clinical trials. We believe that this rational approach will be generalisable to any disease state with underlying microbiome aetiology and will expedite the development of novel microbiome-derived therapeutics to improve human health.

microbiology↗

bioRxiv2021

A lung targeted miR-29 Mimic as a Therapy for Pulmonary Fibrosis

microRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported a systemically delivered miR-29 mimic MRG-201 that reduced fibrosis in animal models, but at doses prohibiting clinical translation. Here, we generated MRG-229, a next-gen miR-29 mimic with improved chemical stability, conjugated with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide). In TGF-b-treated human lung fibroblasts and precision cut lung slices, MRG-229 decreased COL1A1 and ACTA2 gene expression and reduced collagen production. In bleomycin-treated mice, intravenous or subcutaneous delivery of MRG-229 downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, and at clinically relevant doses, MRG-229 was well tolerated, with no adverse findings observed. In human peripheral blood decreased mir-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment. Collectively, our results provide support for the development of MRG-229 as a potential therapy in humans with IPF. One Sentence SummaryOne Sentence Summary: A stabilized, next-generation miR-29 mimic has been developed that demonstrates efficacy at commercially viable doses with a robust safety margin in non-human primates.

molecular biology↗

bioRxiv2019

Identifying and engineering ancient variants of enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)

Ancestral sequence reconstruction is a technique that is gaining widespread use in molecular evolution studies and protein engineering. Accurate reconstruction requires the ability to handle appropriately large numbers of sequences, as well as insertion and deletion ("indel") events, but available approaches exhibit limitations. To address these limitations, we developed Graphical Representation of Ancestral Sequence Predictions (GRASP), which efficiently implements maximum likelihood methods to enable the inference of ancestors of families with more than 10,000 members. GRASP implements partial order graphs (POGs) to represent and infer insertion and deletion events across ancestors, enabling the identification of building blocks for protein engineering. To validate the capacity to engineer novel proteins from realistic data, we predicted ancestor sequences across three distinct enzyme families: glucose-methanol-choline (GMC) oxidoreductases, cytochromes P450, and dihydroxy/sugar acid dehydratases (DHAD). All tested ancestors demonstrated enzymatic activity. Our study demonstrates the ability of GRASP (1) to support large data sets over 10,000 sequences and (2) to employ insertions and deletions to identify building blocks for engineering biologically active ancestors, by exploring variation over evolutionary time. Author summaryMassive sequencing projects expose the extent of natural, genetic diversity. Here, we describe a method with capacity to perform ancestor sequence reconstruction from data sets in excess of 10,000 sequences, poised to recover ancestral diversity, including the evolutionary events that determine present-time biological function and structure. We introduce a novel strategy for suggesting "indel variants" that are distinct from, but can be explored alongside, substitution variants for creating ancestral libraries. We demonstrate how indels can be used as building blocks to form "hybrid ancestors"; based on this strategy, we synthesise ancestor variants, with varying enzymatic activities, for wide-ranging applications in the biotechnology sector.

bioinformatics↗