UNASSIGNED: Alzheimer\'s disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD.
UNASSIGNED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms \'ALZ-801\' or \'valiltramiprosate.\' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate\'s active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aβ42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate\'s phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion.
UNASSIGNED: Valiltramiprosate\'s clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

Parkinson\'s disease (PD) is characterized by an abnormal post-translational modifications (PTM) in amino acid sequence and aggregation of alpha-synuclein (α-Syn) protein. It is generally believed that dopamine (DA) metabolite in dopaminergic (DAergic) neurons promotes the aggregation of toxic α-Syn oligomers and protofibrils, whereas DA inhibits the formation of toxic fibers and even degrades the toxic fibers. Therefore, the study on interaction between DA metabolites and α-Syn oligomers is one of the current hot topics in neuroscience, because this effect may have direct relevance to the selective DAergic neuron loss in PD. Several mechanisms have been reported for DA metabolites induced α-Syn oligomers viz. i) The reactive oxygen species (ROS) released during the auto-oxidation or enzymatic oxidation of DA changes the structure of α-Syn by the oxidation of amino acid residue leading to misfolding, ii) The oxidized DA metabolites directly interact with α-Syn through covalent or non-covalent bonding leading to the formation of oligomers, iii) DA interacts with lipid or autophagy related proteins to decreases the degradation efficiency of α-Syn aggregates. However, there is no clear-cut mechanism proposed for the interaction between DA and α-Syn. However, it is believed that the lysine (Lys) side chain of α-Syn sequence is the initial trigger site for the oligomer formation. Herein, we review different chemical mechanism involved during the interaction of Lys side chain of α-Syn with DA metabolites such as dopamine-o-quinone (DAQ), dopamine-chrome (DAC), dopamine-aldehyde (DOPAL) and neuromelanin. This review also provides the promotive effect of divalent Cu2+ ions on DA metabolites induced α-Syn oligomers and its inhibition effect by antioxidant glutathione (GSH).

The inhaled route is still a relatively novel route for delivering biologics and poses additional challenges to those encountered with inhaled small molecules, further complicating the design and interpretation of toxicology studies. A working group formed to summarize the current knowledge of inhaled biologics across industry and to analyze data collated from an anonymized cross-industry survey comprising 12 inhaled biologic case studies (18 individual inhalation toxicity studies on monoclonal antibodies, fragment antibodies, domain antibodies, oligonucleotides, and proteins/peptides). The output of this working group provides valuable insights into the issues faced when conducting toxicology studies with inhaled biologics, including common technical considerations on aerosol generation, use of young and sexually mature nonhuman primates, pharmacokinetic/pharmacodynamic modeling, exposure and immunogenicity assessment, maximum dose setting, and no observed adverse effect levels determination. Although the current data set is too small to allow firm conclusions, testing of novel biologics remains an active area and is likely to remain so for molecules where delivery via the inhaled route is beneficial. In the future, it is hoped others will continue to share their experiences and build on the conclusions of this review to further improve our understanding of these complex issues and, ultimately, facilitate the safe introduction of inhaled biologics into clinical use.

A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains unresolved. The synthesis of a peptide homologous to residues 106-126 of the human prion protein (PrP106-126), a sequence present in the PrP amyloid protein of Gerstmann-Sträussler-Scheinker syndrome patients, provided a tractable tool for investigating the mechanisms of neurotoxicity. Together with several other discoveries at the beginning of the 1990s, PrP106-126 contributed to underpin the role of amyloid in the pathogenesis of protein-misfolding neurodegenerative disorders. Later, the role of oligomers on one hand and of prion-like spreading of pathology on the other further clarified mechanisms shared by different neurodegenerative conditions. Our original report on PrP106-126 neurotoxicity also highlighted a role for programmed cell death in CNS diseases. In this review, we analyse the prion research context in which PrP106-126 first appeared and the advances in our understanding of prion disease pathogenesis and therapeutic perspectives 25 years later.