Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: Phase 1 trial outcomes

Abstract

ObjectiveThe US Food and Drug Administration–approved trial, “A Phase 1, Open-Label, First-in-Human, Feasibility and Safety Study of Human Spinal Cord-Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis, Protocol Number: NS2008-1,” is complete. Our overall objective was to assess the safety and feasibility of stem cell transplantation into lumbar and/or cervical spinal cord regions in amyotrophic lateral sclerosis (ALS) subjects.MethodsPreliminary results have been reported on the initial trial cohort of 12 ALS subjects. Here, we describe the safety and functional outcome monitoring results for the final trial cohort, consisting of 6 ALS subjects receiving 5 unilateral cervical intraspinal neural stem cell injections. Three of these subjects previously received 10 total bilateral lumbar injections as part of the earlier trial cohort. All injections utilized a novel spinal-mounted stabilization and injection device to deliver 100,000 neural stem cells per injection, for a dosing range up to 1.5 million cells. Subject assessments included detailed pre- and postsurgical neurological outcome measures.ResultsThe cervical injection procedure was well tolerated and disease progression did not accelerate in any subject, verifying the safety and feasibility of cervical and dual-targeting approaches. Analyses on outcome data revealed preliminary insight into potential windows of stem cell biological activity and identified clinical assessment measures that closely correlate with ALS Functional Rating Scale-Revised scores, a standard assessment for ALS clinical trials.InterpretationThis is the first report of cervical and dual-targeted intraspinal transplantation of neural stem cells in ALS subjects. This approach is feasible and well-tolerated, supporting future trial phases examining therapeutic dosing and efficacy.

Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS

“…The HSSC product,17 surgical methods,14, 15 participant selection, immunosuppression regimen, and study activities are previously described 12, 13, 16. Phase 1, conducted at Emory University, followed a “risk escalation” design with 15 participants.…”

“…We completed Phase 112, 13, 14, 15 and 216 HSSC intraspinal transplantation trials in ALS patients. Phase 1 evaluated the feasibility of injecting HSSCs directly into lumbar (L2–L4) or cervical (C3–C5) spinal cord regions in 15 ALS participants following a “risk escalation” paradigm.…”

Part I: Minicircle vector technology limits DNA size restrictions on ex vivo gene delivery using nanoparticle vectors: Overcoming a translational barrier in neural stem cell therapy

“…NSCs can function as a cell source for 'restorative cell therapeutics' in sites of neuropathology (given their capacity for self-renewal and multipotentiality) [1,2]. They create an environment permissive for repair by releasing pro-regenerative and immunosuppressive proteins, and these cells have rapidly progressed to clinical trials for several neurological disorders [3][4][5][6][7].…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…Based on the promising preclinical data mentioned above, a phase I, first-in-human, Food and Drug Administrationapproved clinical trial utilizing NSI-566RSC has recently been completed [14,[87][88][89]91]. In this study, 12 patients underwent unilateral or bilateral lumbar intraspinal transplantation surgeries and 6 patients received unilateral cervical intraspinal transplantation surgeries following a riskescalation design.…”

“…Of note, 3 patients received both lumbar and cervical transplants; therefore, the phase I study involved a total of 15 patients (Table 3). The study demonstrated safety and tolerability of the surgical procedure using a customized injection platform with a floating cannula designed to reduce risk of injury to the spinal cord given cardiorespiratory motion [89,91], and anatomical injection accuracy to the ventral horn was determined using presurgical magnetic resonance imaging evaluation ( Fig. 1; [10]).…”