Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation

• Published in: PloS one Vol. 7; no. 8; p. e42614
• Main Authors: Hefferan, Michael P, Galik, Jan, Kakinohana, Osamu, Sekerkova, Gabriela, Santucci, Camila, Marsala, Silvia, Navarro, Roman, Hruska-Plochan, Marian, Johe, Karl, Feldman, Eva, Cleveland, Don W, Marsala, Martin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20-08-2012; Public Library of Science (PLoS)
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - physiopathology; Amyotrophic Lateral Sclerosis - surgery; Analysis; Anesthesiology; Animals; Axons; Biology; Conduction; Cortex (motor); Development and progression; Electric Stimulation; Electrical resistivity; Electrical stimuli; Evoked Potentials, Motor; Fetuses; Gene therapy; Genetic aspects; Grafting; Humans; Integrity; Ischemia; Laboratories; Life span; Medical research; Medicine; Motor evoked potentials; Motor neurons; Mutation; Neural stem cells; Neural Stem Cells - transplantation; Neurobiology; Neurons; Neurosciences; Paralysis; Pyramidal tracts; Rats; Rats, Transgenic; Rodents; Spinal cord; Spinal Cord - surgery; Spinal cord injuries; Stem Cell Transplantation; Stem cells; Studies; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Superoxides; Synapses - physiology; Thorax; Transplantation; Ventral horn; La Jolla California; Czech Republic; California; Slovakia; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042614

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.
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.
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.