Blood-brain barrier penetration and in vivo activity of an NGF conjugate.
Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.
Friden
P M
PM
Alkermes, Inc., Cambridge, MA 02139.
Walus
L R
LR
Watson
P
P
Doctrow
S R
SR
Kozarich
J W
JW
Bäckman
C
C
Bergman
H
H
Hoffer
B
B
Bloom
F
F
Granholm
A C
AC
D000818:Animals; D000867:Anterior Chamber / Q000378:metabolism; D000906:Antibodies / Q000378:metabolism*; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002196:Capillaries; D002460:Cell Line; D003432:Cross-Linking Reagents; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D007150:Immunohistochemistry; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000276:immunology*
D000906:Antibodies; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D009414:Nerve Growth Factors; D011990:Receptors, Transferrin