Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis.
When fused with the protein transduction domain (PTD) derived from the human immunodeficiency virus TAT protein, proteins can cross the blood-brain barrier and cell membrane and transfer into several tissues, including the brain, making protein therapy feasible for various neurological disorders. We have constructed a powerful antiapoptotic modified Bcl-X(L) protein (originally constructed from Bcl-X(L)) fused with PTD derived from TAT (TAT-modified Bcl-X(L)), and, to examine its clinical effectiveness in a mouse model of familial amyotrophic lateral sclerosis (ALS), transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation were treated by intrathecal infusion of TAT-modified Bcl-X(L). We demonstrate that intrathecally infused TAT-fused protein was effectively transferred into spinal cord neurons, including motor neurons, and that intrathecal infusion of TAT-modified Bcl-X(L) delayed disease onset, prolonged survival, and improved motor performance. Histological studies show an attenuation of motor neuron loss and a decrease in the number of cleaved caspase 9-, cleaved caspase 3-, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the lumbar cords of TAT-modified Bcl-X(L)-treated G93A mice. Our results indicate that intrathecal protein therapy using a TAT-fused protein is an effective clinical tool for the treatment of ALS.
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikata-cho, Okayama, Japan. yasuyuki@cc.okayama-u.ac.jp
Yasuyuki
Y
Ohta
Tatsushi
T
Kamiya
Makiko
M
Nagai
Tetsuya
T
Nagata
Nobutoshi
N
Morimoto
Kazunori
K
Miyazaki
Tetsuro
T
Murakami
Tomoko
T
Kurata
Yasushi
Y
Takehisa
Yoshio
Y
Ikeda
Sadamitsu
S
Asoh
Shigeo
S
Ohta
Koji
K
Abe
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D015696:Gene Products, tat; D006801:Humans; D020287:In Situ Nick-End Labeling; D007278:Injections, Spinal; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D051020:bcl-X Protein / Q000008:administration & dosage*
D015696:Gene Products, tat; D051020:bcl-X Protein