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Introduction: 2022 was a landmark year with two adeno-associated viral vectors (AAVs) receiving conditional marketing authorization from EMA for the treatment of persons with severe haemophilia A and severe to moderately severe haemophilia B and a third in 2024. Gene therapy is a transformative, irreversible treatment with long-lasting effects, necessitating development of new clinical pathways to ensure optimal outcomes., Aim: To develop a consensus framework and service specification for delivery of AAV gene therapy for haemophilia in adults within the UK using the hub-and-spoke model proposed by the European Association of Haemophilia and Allied Disorders and the European Haemophilia Consortium., Methods: The UK Haemophilia Centre Doctors Organisation (UKHCDO) set up a working party to develop expert consensus guidance, working with NHS England to ensure alignment with NHS England commissioning and the national service specification., Results: These guidelines detail the patient pathway, counselling and governance requirements for the hub-and-spoke model. The national service specification requires the hub site to manage governance for AAV-based gene therapy. Proposed regional and national multidisciplinary teams will harmonize clinical practices incorporating expertise from various specialities and professional groups. Key requirements identified include standardized documentation and multidisciplinary collaboration. Nationally agreed patient information and counselling checklists will streamline the informed consent process and facilitate data collection for long-term safety and efficacy monitoring., Conclusion: These guidelines provide a structured framework for the delivery of liver-directed gene therapy. Whilst specific to the United Kingdom they provide a framework for the implementation of gene therapy in other countries for haemophilia and other monogenic disorders., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Small tripeptides composed entirely of β 3 -amino acids have been shown to self-assemble into fibres following acylation of the N-terminus. Given the use of Fmoc as a strategy to initiate self-assembly in α-peptides, we hypothesized that the acyl cap can be replaced by an Fmoc without perturbation to the self-assembly and enable simpler synthetic protocols. We therefore replaced the N -acyl cap for an Fmoc group and herein we show that these Fmoc-protected β 3 -peptides produce regular spherical particles, rather than fibrous structures, that are stable and capable of encapsulating cargo. We then demonstrated that these particles were able to deliver cargo to cells without any obvious signs of cytotoxicity. This is the first description of such regular nanoparticles derived from Fmoc-protected β 3 -peptides., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

A synthetic strategy for conjugating small molecules and peptide-based therapeutics, via a cleavable ester bond, to a lipidated β 3 -tripeptide is presented. The drug-loaded β 3 -peptide was successfully co-assembled with a functionally inert lipidated β 3 -tripeptide to form a hydrogel. Quantitative release of lactose from the hydrogel, by the action of serum esterases, is demonstrated over 28 days. The esterase-mediated sustained release of the bioactive brain-derived neurotrophic factor (BDNF) peptide mimics from the hydrogel resulted in increased neuronal survival and normal neuronal function of peripheral neurons. These studies define a versatile strategy for the facile synthesis and co-assembly of self-assembling β 3 -peptide-based hydrogels with the ability to control drug release using endogenous esterases with potential in vivo applications for sustained localized drug delivery.

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 Diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.

The enzyme 2,4′-dihydroxyacetophenone dioxygenase (or DAD) catalyses the conversion of 2,4′-dihydroxyacetophenone to 4-hydroxybenzoic acid and formic acid with the incorporation of molecular oxygen. Whilst the vast majority of dioxygenases cleave within the aromatic ring of the substrate, DAD is very unusual in that it is involved in C-C bond cleavage in a substituent of the aromatic ring. There is evidence that the enzyme is a homotetramer of 20.3 kDa subunits each containing nonhaem iron and its sequence suggests that it belongs to the cupin family of dioxygenases. By the use of limited chymotrypsinolysis, the DAD enzyme from Alcaligenes sp. 4HAP has been crystallized in a form that diffracts synchrotron radiation to a resolution of 2.2 Å. [ABSTRACT FROM AUTHOR]

Purpose: The New Mexico Graduation Reality and Dual-role Skills (GRADS) program provides services for expectant and parenting students at high schools. The GRADS program has operated since 1989, serving more than 17,000 youth. This study summarizes the GRADS program model and program administrators' lessons learned from implementing this comprehensive, large-scale program., Description: The GRADS program is a multicomponent intervention that can include a classroom intervention, case management, linkages to child care and health care, and support for young fathers. The program aims to support expectant and parenting youth in finishing high school, delaying a repeat pregnancy, promoting health outcomes for their children, and preparing for college and career. This study presents program administrators' lessons learned to increase understanding of how to implement a statewide program to support expectant and parenting students., Assessment: During the 2010-2017 school years, the GRADS program operated in 26-31 sites each year, serving a total of 2691 parenting youth. Program administrators identified lessons learned from implementing the GRADS program during that period of expansion, including allowing variation across sites based on resources and needs, providing centralized implementation support, fostering buy-in from school and district leaders, and collecting consistent data to better understand participant outcomes., Conclusions: Although not based on a rigorous impact or implementation study, this article provides lessons learned from a statewide, school-based program that may be a promising way to serve a large number of expectant and parenting youth and help them overcome challenges for completing high school.

The chemical synthesis of cyclic peptides is a well-established area of research. This has been further expanded by development of bio-orthogonal reactions that enable access to peptides of greater structural complexity. One approach utilizes 1,3-dichloroacetone to selectively link free cysteine side-chains with an acetone-like bridge via an S N 2 reaction. Here, we have used this reaction to dimerize cyclic peptide monomers to create novel bicyclic dimeric peptides. We investigated a range of reaction parameters to identify the optimal dimerization conditions for our model systems. One of the acetone-linked dimeric peptides was analyzed for proteolytic stability in human serum and was observed to still be fully intact after 48 h. This study provides valuable insights into the application of 1,3-dichloroacetone as a tool in the synthesis of complex, multicyclic peptides., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)