Treatment of experimental autoimmune encephalomyelitis with antisense oligonucleotides against the low affinity neurotrophin receptor.
Upregulated expression of the low-affinity neurotrophin receptor (p75) in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) has recently been demonstrated. To investigate whether p75 plays a role in disease pathogenesis, we adopted a gene therapy approach, utilizing antisense oligonucleotides to downregulate p75 expression during EAE. Phosphorothioate antisense oligonucleotides (AS), nonsense oligonucleotides (NS) or phosphate buffered saline (PBS) were injected daily for 18 days after immunization of SJL/J (H-2s)-mice with myelin proteolipid protein (PLP) peptide 139-151. In the AS group, there was a statistically significant reduction in both the mean maximal disease score (1.85 in the AS, 2.94 in the NS and 2.75 in the PBS-groups, respectively, P < 0.025) and in the cumulative disease incidence ( approximately 60% in the AS group and approximately 90% in the control groups). Histological and immunohistochemical analysis showed reduced inflammation and demyelination, as well as reduced p75 expression at the blood-brain barrier (BBB) in the AS-treated mice in comparison with both control groups. There was no difference, however, in p75 expression on neural cells within the CNS between the three groups of mice. We conclude that p75 could play a proactive role in the pathogenesis of EAE and may exert its effect at the level of the BBB.
Soilu-Hänninen
M
M
The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
Epa
R
R
Shipham
K
K
Butzkueven
H
H
Bucci
T
T
Barrett
G
G
Bartlett
P F
PF
Kilpatrick
T J
TJ
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D015316:Genetic Therapy; D051379:Mice; D008815:Mice, Inbred Strains; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016896:Treatment Outcome
D016376:Oligonucleotides, Antisense; D020800:Receptor, Nerve Growth Factor