Vol. 297, Issue 3, 1113-1121, June 2001

Delivery across the Blood-Brain Barrier of Antisense Directed against Amyloid : Reversal of Learning and Memory Deficits in Mice Overexpressing Amyloid Precursor Protein

William A. Banks, Susan A. Farr, Waseem Butt, Vijaya B. Kumar, Mark W. Franko and John E. Morley

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

Amyloid  protein (A) 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 A, can be reversed with i.c.v. injections of an A antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with ³²P (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 µl/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.