Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein.
Amyloid beta protein (Abeta) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Abeta, can be reversed with i.c.v. injections of an Abeta antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with (32)P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 +/- 0.39 microl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken up by each gram of brain (0.865 +/- 0.115%) being about 1/100 of the i.c.v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.
Banks
W A
WA
Geriatric Research, Education and Clinical Center, St. Louis Veterans Affairs Medical Center and Department of Internal Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Farr
S A
SA
Butt
W
W
Kumar
V B
VB
Franko
M W
MW
Morley
J E
JE
D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007859:Learning Disabilities / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D020127:Recovery of Function / Q000187:drug effects; D013873:Thionucleotides; D014018:Tissue Distribution; D016896:Treatment Outcome
D016564:Amyloid beta-Protein Precursor; C428115:Olg antisense phosphorothioate oligonucleotide; D016376:Oligonucleotides, Antisense; D009946:Organothiophosphorus Compounds; D013873:Thionucleotides