Post-Baccalaureate Researcher Sanford Burnham Prebys Medical Discovery Institute La Jolla, California, United States
Abstract: Amyotrophic Lateral Sclerosis (ALS) is an incurable lethal neurodegenerative disease caused by motoneuron (MNs) death leading to loss of skeletal muscle innervation, resulting in paralysis & respiratory failure in ALS patients. We previously published results showing human neural stem cells (hNSCs) delayed ALS onset & prolonged life by as much as 300% in the SOD1 mouse when injected at 4 cardinal life-preserving locations along the neuraxis, including cervical spinal cord (SC) that mediates respiration. Mechanism of action was in part via secretion of neuroprotective factors, inhibition of host NSCs from elaborating toxic astrocytes, & supplying trophic astrocytes & gray matter oligodendrocytes. The greater the expanse of donor hNSCs, the more MNs & longer life were preserved. We previously reported that a novel synthetic peptide (“SDV1a”) selectively engages the CXCR4 binding pocket on NSCs & can act as a chemoattractant directing transplanted hNSCs to desired CNS regions. Last year we presented findings from a novel minimally-invasive non-surgical route-of-administration (ROA) for hNSCs –cell suspension injection into the cisterna magna (CM) & SDV1a into the lumbar SC of pre-symptomatic SOD1 mice (60-70 days-old) to direct hNSCs throughout the SC from rostral-to-caudal, allowing ventral horn entry via CSF space by “crawling along” ventral roots & being attracted toward MNs. Preliminary results suggest this approach may be safe, effective & sufficiently non-traumatic that hNSCs can be re-administered when symptoms develop/condition begins to deteriorate. Initial hNSCs dosing allowed SOD1 mice to live at least 3.5 months longer than untreated controls. Re-dosing mice (with 1x106 hNSCs via CM + SDV1a intra-SC) when symptoms worsened (by 20% on rotarod test & BBB scale) extended life by at least another 4-5 months (when experiment was terminated, despite animals remaining minimally symptomatic) to perform MN counts. These preliminary findings suggest long-term safety of this novel ROA in SOD1 mice. By studying the efficacy, safety, & minimal discomfort of re-dosing SOD1 mice at symptomatic deterioration, we may suggest an atraumatic, well-tolerated approach to treat ALS patients recurrently when symptoms worsen, potentially extending their lives with manageable symptoms & improving quality-of-life.
Funding Source: California Institute for Regenerative Medicine (CIRM) & SENS Research Foundation.
