Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria.

Phenylketonuria (PKU) is a genetically inherited disease caused by a mutation of the gene encoding phenylalanine hydroxylase (PAH) and is the most common inborn error of amino acid metabolism. A deficiency of PAH leads to increased blood and brain levels of phenylalanine (Phe), which may cause permanent neurocognitive symptoms and developmental delays if untreated. Current management strategies for PKU consist of early detection through neonatal screening and implementation of a restrictive diet with minimal amounts of natural protein in combination with Phe-free supplements and low-protein foods to meet nutritional requirements. For milder forms of PKU, oral treatment with synthetic sapropterin (BH4), the cofactor of PAH, may improve metabolic control of Phe and allow for more natural protein to be included in the patient's diet. For more severe forms, daily injections of pegvaliase, a PEGylated variant of phenylalanine ammonia-lyase (PAL), may allow for normalization of blood Phe levels. However, the latter treatment has considerable drawbacks, notably a strong immunogenicity of the exogenous enzyme and the attached polymeric chains. Research for novel therapies of PKU makes use of innovative materials for drug delivery and state-of-the-art protein engineering techniques to develop treatments which are safer, more effective, and potentially permanent.

Template-Based Porous Hydrogel Microparticles as Carriers for Therapeutic Proteins.

Hydrogels have been extensively researched for over 60 years for their limitless applications in biomedical research. In this study, porous hydrogel microparticles (PHMPs) made of poly(ethylene glycol) diacrylamide were investigated for their potential as a delivery platform for therapeutic proteins. These particles are made using hard calcium carbonate (CaCO3) templates, which can easily be dissolved under acidic conditions. After optimization of the synthesis processes, both CaCO3 templates and PHMPs were characterized using a wide range of techniques. Then, using an array of proteins with different physicochemical properties, the encapsulation efficiency of proteins in PHMPs was evaluated under different conditions. Strategies to enhance protein encapsulation via modulation of particle surface charge to increase electrostatic interactions and conjugation using EDC/NHS chemistry were also investigated. Conjugation of bovine serum albumin to PHMPs showed increased encapsulation and diminished release over time, highlighting the potential of PHMPs as a versatile delivery platform for therapeutic proteins such as enzymes or antibodies.

Therapeutic nanotechnologies for Alzheimer's disease: A critical analysis of recent trends and findings.

Alzheimer's Disease (AD) is an irreversible neurodegenerative disease for which no modifying therapies are presently available. Besides the identification of pathological targets, AD presents numerous clinical and pharmacological challenges such as efficient active delivery to the central nervous system, cell targeting, and long-term dosing. Nanoparticles have been explored to overcome some of these challenges as drug delivery vehicles or drugs themselves. However, early promises have failed to materialize as no nanotechnology-based product has been able to reach the market and very few have moved past preclinical stages. In this review, we perform a critical analysis of the past decade's research on nanomedicine-based therapies for AD at the preclinical and clinical stages. The main obstacles to nanotechnology products and the most promising approaches were also identified, including renewed promise with gene editing, gene modulation, and vaccines.

Identification of a superagonist variant of the immunodominant Yellow fever virus epitope NS4b 214-222 by combinatorial peptide library screening.

The CD8 T cell response to the HLA-A2-restricted epitope LLWNGPMAV (LLW) of the non-structural protein 4b of Yellow Fever Virus (YFV) is remarkably immunodominant, highly prevalent and powerful in YFV-vaccinated humans. Here we used a combinatorial peptide library screening in the context of an A2/LLW-specific CD8 T cell clone to identify a superagonist that features a methionine to isoleucine substitution at position 7. Based on in silico modeling, the functional enhancement of this LLW-7I mutation was associated with alterations in the structural dynamics of the peptide in the major histocompatibility complex (pMHC) binding with the T cell receptor (TCR). While the TCR off-rate of LLW-7I pMHC is comparable to the wild type peptide, the rigidity of the 7I peptide seems to confer less entropy loss upon TCR binding. This LLW-7I superagonist is an example of improved functionality in human CD8 T cells associated with optimized ligand rigidity for TCR binding and not with changes in TCR:pMHC off-rate kinetics.

Periphery-confined particulate systems for the management of neurodegenerative diseases and toxicity: Avoiding the blood-brain-barrier challenge.

The blood-brain barrier prevents passage of large and hydrophilic molecules, undermining efforts to deliver most active molecules, proteins and other macromolecules. To date, nanoparticle-assisted delivery has been extensively studied to overcome this challenge but with limited success. On the other hand, for certain brain therapeutic applications, periphery-confined particles could be of immediate therapeutic usefulness. The modulation of CNS dysfunctions from the peripheral compartment is a promising approach, as it does not involve invasive interventions. From recent studies, three main roles could be identified for periphery-confined particles: brain tissue detoxification via the "sink-effect"; a "circulating drug-reservoir" effect to improve drug delivery to brain tissues, and finally, brain vascular endothelium targeting to diagnose or heal vascular-related dysfunctions. These applications are much easier to implement as they do not involve complex therapeutic and targeting strategies and do not require crossing biological barriers. Micro/nano-devices required for such applications will likely be simpler to synthesize and will involve fewer complex materials. Moreover, peripheral particles are expected to be less prone to neurotoxicity and issues related to their diffusion in confined space.