Emerging Safety of Intramedullary Transplantation of Human Neural Stem Cells in Chronic Cervical and Thoracic Spinal Cord Injury

Levi, Allan D.; Okonkwo, David O.; Park, Paul; Jenkins, Arthur L.; Kurpad, Shekar N.; Parr, Ann M.; Ganju, Aruna; Aarabi, Bizhan; Kim, Dong H.; Casha, Steven; Fehlings, Michael G.; Harrop, James S.; Anderson, Kim D.; Gage, Allyson; Hsieh, Jane; Huhn, Stephen L.; Curt, Armin; Guzman, Raphael

doi:10.1093/neuros/nyx250

Cited by 124 publications

(89 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Banked NSCs can also induce functional myelin in a severe demyelination model (Uchida et al., 2012), the shiverer mouse, and restore motor function in a mouse model of spinal cord injury ( Cummings et al., 2005, Salazar et al., 2010). The proof-of-concept data in pre-clinical studies led to other phase I or II studies with NSCs in the hypomyelinating disease, Pelizaeus-Merzbacher disease (PMD) (Gupta et al., 2012), traumatic thoracic and cervical spinal cord injury (Levi et al., 2017), and age-related macular degeneration (clinical trial number NCT01632527). These clinical studies demonstrated the safety, feasibility, long-term survival, and early evidence of efficacy of using banked NSCs in treating neurologic diseases.…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Genome Engineering in Engraftable Human Brain-Derived Neural Stem Cells

et al. 2019

View full text Add to dashboard Cite

Summary Human neural stem cells (NSCs) offer therapeutic potential for neurodegenerative diseases, such as inherited monogenic nervous system disorders, and neural injuries. Gene editing in NSCs (GE-NSCs) could enhance their therapeutic potential. We show that NSCs are amenable to gene targeting at multiple loci using Cas9 mRNA with synthetic chemically modified guide RNAs along with DNA donor templates. Transplantation of GE-NSC into oligodendrocyte mutant shiverer-immunodeficient mice showed that GE-NSCs migrate and differentiate into astrocytes, neurons, and myelin-producing oligodendrocytes, highlighting the fact that GE-NSCs retain their NSC characteristics of self-renewal and site-specific global migration and differentiation. To show the therapeutic potential of GE-NSCs, we generated GALC lysosomal enzyme overexpressing GE-NSCs that are able to cross-correct GALC enzyme activity through the mannose-6-phosphate receptor pathway. These GE-NSCs have the potential to be an investigational cell and gene therapy for a range of neurodegenerative disorders and injuries of the central nervous system, including lysosomal storage disorders.

show abstract

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Genome Engineering in Engraftable Human Brain-Derived Neural Stem Cells

et al. 2019

View full text Add to dashboard Cite

show abstract

“…One clinical trial reported one subdural hematoma in 18 patients who underwent intraparenchymal stem cell transplantation using the Pittsburg cannula [6] and one in 13 patients who underwent intraparenchymal human neural stem cell transplantation [8]. In contrast, Levi et al showed no needle (30-gauge) complication when injecting human CNS stem cells in 29 patients with cervical and thoracic cord injury, with four to eight sites and a depth of 3-4 mm from the spinal cord surface being selected for injection [16]. However, the possibility of intraparenchymal hemorrhage caused by the injection cannula should not be underestimated, as it may cause catastrophic complications.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease

Kawabori

Tanimori

Kitta

et al. 2020

Stem Cells International

View full text Add to dashboard Cite

Cell therapy for central nervous system (CNS) disorders is beginning to prove its safety and efficiency. Intraparenchymal transplantation can be an option for cell delivery; however, one concern regarding this method is that the transplantation cannula may cause additional brain injuries. These include vessel damage, which results in brain hemorrhage, and clogging of the cannula by brain debris and/or cell clusters, which requires replacement of the cannula or forced injection causing jet flow of the cell suspension. We compared cannulas for cell delivery used in clinical trials, the Pittsburg and Mizuho cannulas, to a newly designed one, MK01, to assess their usability. MK01 has a spherical-shaped tip with a fan-like open orifice on the side of the cannula, which prevents vessel damage, clogging of brain debris, and jet flow phenomenon. We compared the extent of rat cervical and abdominal arterial damage with the cannula, the amount of debris in the cannula, the force needed to cause jet flow, and cell viability. While the viability of cells passed through the cannulas was almost the same among cannulas (approximately 95%), the Pittsburg cannula caused cervical arterial injury and subsequent hemorrhage, as it required a significantly smaller force to penetrate the arterial wall. Moreover, the Pittsburg cannula, but not the Mizuho and MK01 cannulas, showed high frequency of brain debris in the needle tip (approximately 80%) after brain puncture. While jet flow of the injection liquid was observed even when using smaller forces in the Pittsburg and Mizuho cannulas, MK01 constantly showed low jet flow occurrence. Thus, MK01 seems to be safer than the previously reported cannulas, although further investigation is necessary to validate its safety for clinical use.

show abstract

“…The trials were terminated early in 2016; according to a recent report, there was no significant increase in the rate of serious adverse events with escalating doses, suggesting that the therapy was well tolerated. 105 Neuralstem Inc. is now recruiting for an open-label, single-site phase I (N = 8; NCT01772810) safety study of human spinal cord-derived NSCs in individuals with 1-to 2-yearold AIS grade A injuries at C5-7 or T2-12. Results are expected in 2022.…”

Section: Neural Stem Cellsmentioning

confidence: 99%

Time is spine: a review of translational advances in spinal cord injury

Badhiwala

Ahuja

Fehlings

2019

Journal of Neurosurgery: Spine

208

186

View full text Add to dashboard Cite

Acute traumatic spinal cord injury (SCI) is a devastating event with far-reaching physical, emotional, and economic consequences for patients, families, and society at large. Timely delivery of specialized care has reduced mortality; however, long-term neurological recovery continues to be limited. In recent years, a number of exciting neuroprotective and regenerative strategies have emerged and have come under active investigation in clinical trials, and several more are coming down the translational pipeline. Among ongoing trials are RISCIS (riluzole), INSPIRE (Neuro-Spinal Scaffold), MASC (minocycline), and SPRING (VX-210). Microstructural MRI techniques have improved our ability to image the injured spinal cord at high resolution. This innovation, combined with serum and cerebrospinal fluid (CSF) analysis, holds the promise of providing a quantitative biomarker readout of spinal cord neural tissue injury, which may improve prognostication and facilitate stratification of patients for enrollment into clinical trials. Given evidence of the effectiveness of early surgical decompression and growing recognition of the concept that “time is spine,” infrastructural changes at a systems level are being implemented in many regions around the world to provide a streamlined process for transfer of patients with acute SCI to a specialized unit. With the continued aging of the population, central cord syndrome is soon expected to become the most common form of acute traumatic SCI; characterization of the pathophysiology, natural history, and optimal treatment of these injuries is hence a key public health priority. Collaborative international efforts have led to the development of clinical practice guidelines for traumatic SCI based on robust evaluation of current evidence. The current article provides an in-depth review of progress in SCI, covering the above areas.

show abstract

Emerging Safety of Intramedullary Transplantation of Human Neural Stem Cells in Chronic Cervical and Thoracic Spinal Cord Injury

Abstract: A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

Cited by 124 publications

References 38 publications

CRISPR/Cas9 Genome Engineering in Engraftable Human Brain-Derived Neural Stem Cells

CRISPR/Cas9 Genome Engineering in Engraftable Human Brain-Derived Neural Stem Cells

Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease

Time is spine: a review of translational advances in spinal cord injury

Contact Info

Product

Resources

About