Novel approaches to treatment of autoimmune neuroinflammation and lessons for drug development.
Drug development, and especially that intended for central nervous system (CNS) disorders, still poses a challenge. We investigated both the use of bifunctional compounds designed for multiple targeting and enhanced CNS permeability, and of recombinant alpha-fetoprotein (AFP), a natural pregnancy-associated immunomodulating protein for the treatment of CNS inflammation. Bifunctional compounds showed a novel pharmacokinetic profile due to the conjugation, yet retained, and even improved pharmacodynamics. AFP was well tolerated and decreased various aspects of neuroinflammation, including disease severity, axonal loss and damage, T-cell reactivity, and antigen presentation. Our results show that both strategies may serve as future drug modalities.
Nizri
Eran
E
Laboratory of Neuroimmunology, Department of Neurology, Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Irony-Tur-Sinai
Michal
M
Grigoriadis
Nikolaos
N
Abramsky
Oded
O
Amitai
Gabi
G
Brenner
Talma
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000627:therapeutic use; D015394:Molecular Structure; D020078:Neurogenic Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents