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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder in which the loss of upper and lower motor neurons produces progressive weakness and eventually death. In the decades since the approval of riluzole, the only US Food and Drug Administration-approved medication to moderately slow progression of ALS, no new therapeutics have arisen to alter the course of the disease. This is partly due to our incomplete understanding of the complex pathogenesis of motor neuron degeneration. Stem cells have emerged as an attractive option in treating ALS, because they come armed with equally complex cellular machinery and may modulate the local microenvironment in many ways to rescue diseased motor neurons. Various stem cell types are being evaluated in preclinical and early clinical applications; here, we review the preclinical strategies and advances supporting the recent clinical translation of neural progenitor cell therapy for ALS. Specifically, we focus on the use of spinal cord neural progenitor cells and the pipeline starting from preclinical studies to the designs of phase I and IIa clinical trials involving direct intraspinal transplantation in humans.

There is growing interest in the use of stem cells1–10 as a therapy in amyotrophic lateral sclerosis (ALS), a lethal neurological disorder characterized by the degeneration of motor neurons. Stem cells offer a means to replace lost cells, provide neurotrophic support, and improve the diseased microenvironment.1,7–10 Preclinical in vitro and in vivo evidence supports the therapeutic translation of stem cells,9 and studies by our group and others demonstrate that human spinal stem cells (HSSCs) produce protective growth factor profiles, differentiate into neurons, form synapses with host motor neurons, and have beneficial effects after intraspinal transplantation in G93A-SOD1 rats, an established model of ALS.2–6 In 2009, the US Food and Drug Administration (FDA) approved a phase 1 clinical trial examining the safety and feasibility of HSSC injections into the spinal cords of 18 ALS subjects. HSSCs were delivered using a novel intraspinal stabilization and injection device developed by our group.11–14 The first 12 trial subjects, representing Cohorts A to C, received HSSC transplants into the L2–L4 lumbar segments of the spinal cord. Group A subjects were nonambulatory and received 5 unilateral (A1, n = 3) or 10 total bilateral (A2, n = 3) lumbar injections. Subjects in Groups B and C were ambulatory and received 5 unilateral (n = 3) or 10 total bilateral (n = 3) lumbar injections, respectively. As previously described, interim results from these first 12 subjects demonstrated no serious adverse events associated with HSSC transplantation.15,16 Those encouraging results along with the critical need to maintain respiratory function in ALS subjects enabled FDA approval to complete HSSC injections into C3–C5 cervical segments of the spinal cord, the region where motor neurons involved in diaphragmatic function reside. To support these injections, the lumbar stabilization and injection device was adapted and optimized for cervical intraspinal HSSC delivery.12–14 Ambulatory subjects in Groups D (n = 3) and E (n = 3) received 5 unilateral cervical injections. Based on previous preclinical data demonstrating enhanced therapeutic efficacy of HSSC transplantation when injections were targeted to multiple spinal cord segments,2,4 subjects in Group E were the same subjects who previously received bilateral lumbar injections as part of Group C. This cohort represents the first examination of the feasibility of targeting both lumbar and cervical spinal cord segments in ALS subjects in separate surgeries. The phase 1 trial consisting of 18 intraspinal transplantation surgeries in 15 ALS subjects was completed in May 2013. Here, we present the functional outcome data from the 6 subjects undergoing cervical stem cell transplantation surgery, including 3 subjects receiving both bilateral lumbar and unilateral cervical HSSC transplants. Data are also presented from the continued follow-up of the first 12 subjects receiving lumbar intraspinal HSSC transplants. Overall, results demonstrate that HSSCs can be safely transplanted into both lumbar and/or cervical human spinal cord segments, warranting future trial phases focused on cellular dosing and therapeutic efficacy.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder in which the loss of upper and lower motor neurons produces progressive weakness and eventually death. In the decades since the approval of riluzole, the only US Food and Drug Administration-approved medication to moderately slow progression of ALS, no new therapeutics have arisen to alter the course of the disease. This is partly due to our incomplete understanding of the complex pathogenesis of motor neuron degeneration. Stem cells have emerged as an attractive option in treating ALS, because they come armed with equally complex cellular machinery and may modulate the local microenvironment in many ways to rescue diseased motor neurons. Various stem cell types are being evaluated in preclinical and early clinical applications; here, we review the preclinical strategies and advances supporting the recent clinical translation of neural progenitor cell therapy for ALS. Specifically, we focus on the use of spinal cord neural progenitor cells and the pipeline starting from preclinical studies to the designs of phase I and IIa clinical trials involving direct intraspinal transplantation in humans.