title: Vascular physiology and protein disposition in a preclinical model of neurodegeneration.
abstract: The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., (99m)Tc-HMPAO) and the polar ionic tracer, rubidium-86 chloride ((86)RbCl), were measured following intravenous injection in SOD1(G93A) and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of (99m)Tc-labeled red blood cells as a blood pool marker. Both the antibody and (86)Rb were able to cross the blood-spinal cord barrier in SOD1(G93A) mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1(G93A) mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently collect an abundance of physiological information, including the degree and regional extent of blood-CNS barrier permeability, in a preclinical model of neurodegeneration.
authors: Preclinical and Translational Pharmacokinetics, Genentech Research and Early Development, South San Francisco, California 94080, United States. boswell.andy@gene.com
authors: C Andrew
authors: CA
authors: Boswell
authors: Eduardo E
authors: EE
authors: Mundo
authors: Bernadette
authors: B
authors: Johnstone
authors: Sheila
authors: S
authors: Ulufatu
authors: Michelle G
authors: MG
authors: Schweiger
authors: Daniela
authors: D
authors: Bumbaca
authors: Paul J
authors: PJ
authors: Fielder
authors: Saileta
authors: S
authors: Prabhu
authors: Leslie A
authors: LA
authors: Khawli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001810:Blood Volume; D001812:Blood-Brain Barrier / Q000502:physiology; D002560:Cerebrovascular Circulation; D002712:Chlorides / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000503:physiopathology*; D021381:Protein Transport; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012413:Rubidium / Q000493:pharmacokinetics; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics; D013482:Superoxide Dismutase / Q000235:genetics; D019690:Technetium Tc 99m Exametazime / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D002712:Chlorides; D007074:Immunoglobulin G; D019275:Radiopharmaceuticals; D012414:Rubidium Radioisotopes; D019690:Technetium Tc 99m Exametazime; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D012413:Rubidium; C032710:rubidium chloride