Alzheimer Disease: Piovesan P

Bauer M, Langer O, Dal-Bianco P, Karch R, Brunner M, Abrahim A, Lanzenberger R, Hofmann A, Joukhadar C, Carminati P, Ghirardi O, Piovesan P, Forloni G, Corrado ME, Lods N, Dudczak R, Auff E, Kletter K, Müller M. · Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna, Vienna, Austria. · Clin Pharmacol Ther. · Pubmed #16952488 No free full text.

Abstract: This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.

Rossi M, Piovesan P, Ghirardi O, Mastroianni D, Bombardi V, Battistini L, Cencioni MT, Capobianco D, Borsini F, Colombo M, Verdoliva A. · Tecnogen S.p.A., R&D, Caserta, Italy. · Mol Immunol. · Pubmed #19535144 No free full text.

Abstract: The most promising approach in Alzheimer disease immunotherapy is represented by amyloid beta derivatives with low intrinsic neurotoxicity and minimal overall T cell responses. To avoid toxicity and autoimmune response, we have designed a new class of Abeta derivatives through segmentation of the original Abeta[1-42] peptide and application of the glycine substitution modification technology. Abeta[1-16], Abeta[13-28] and Abeta[25-42] fragments were selected in order to retain the major immunogenic sites of the Abeta[1-42] peptide. All peptides showed comparable immunogenicity, and raised antibodies were all able to cross-recognize both Abeta[1-42] and Abeta[1-40] synthetic amyloid forms. Polyclonal antibodies produced against the simplified variants were able to recognize the parent peptide, but not the opposite simplified forms, in strict agreement with the model of independent surfaces of recognition. All Abeta simplified derivatives showed reduced fibrillogenic properties, thus underlining that the introduction of glycine residues in alternating positions allows to obtain modified peptides maintaining the main immunogenic properties of the parent peptides, but with reduced ability to adopt a beta-sheet conformation and therefore a much lower risk of toxicity in humans. In addition, in vitro studies on peripheral blood mononuclear cells (PBMCs) from healthy donors showed that only the Abeta[13-28]+G peptide failed to induce IFN-gamma production, thus suggesting that this molecule could represent a good candidate for potentially safer vaccine therapy to reduce amyloid burden in Alzheimer's disease instead of using toxic Abeta[1-42].