Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.
BACKGROUND
Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals.


RESULTS
Presymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A) rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A) rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A) rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65%) loss of large caliber descending motor axons.


CONCLUSIONS
These data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.
Neuroregeneration Laboratory, Department of Anesthesiology, University of California San Diego, La Jolla, California, USA.
Michael P
MP
Hefferan
Jan
J
Galik
Osamu
O
Kakinohana
Gabriela
G
Sekerkova
Camila
C
Santucci
Silvia
S
Marsala
Roman
R
Navarro
Marian
M
Hruska-Plochan
Karl
K
Johe
Eva
E
Feldman
Don W
DW
Cleveland
Martin
M
Marsala
D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology / Q000601:surgery*; D000818:Animals; D004558:Electric Stimulation; D019054:Evoked Potentials, Motor; D006801:Humans; D009154:Mutation; D058953:Neural Stem Cells / Q000637:transplantation*; D051381:Rats; D055647:Rats, Transgenic; D013116:Spinal Cord / Q000601:surgery*; D033581:Stem Cell Transplantation; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000502:physiology
C000606290:SOD1 protein, human; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1