Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats

Xu, Leyan; Shen, Peilin; Hazel, Thomas G.; Johe, Karl; Koliatsos, Vassilis E.

doi:10.1016/j.neulet.2011.03.017

Cited by 84 publications

(84 citation statements)

References 35 publications

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“…This approach is supported by in vitro and in vivo preclinical studies5, 6, 7, 8, 9 and demonstrated safety of HSSC intraspinal transplantation in Gottingen minipigs,10, 11 data which secured Food & Drug Administration approval to examine HSSC intraspinal transplantation in ALS patients.…”

Section: Introductionmentioning

confidence: 93%

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

Goutman

Brown

Glass

et al. 2018

Ann Clin Transl Neurol

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ObjectiveIntraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs.MethodsSurvival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20.ResultsSurvival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study.InterpretationComparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study.

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Section: Introductionmentioning

confidence: 93%

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

Goutman

Brown

Glass

et al. 2018

Ann Clin Transl Neurol

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“…It still remains to be seen whether stem cell transplantation will positively affect the disease course in ALS patients. However, preclinical studies suggest that stem cells can significantly impact ALS including our own studies using human glial-restricted progenitors which have recently received IND approval (Lepore et al, 2008;Xu et al, 2006Xu et al, , 2011. Additionally, our knowledge of the disease has advanced significantly with the recent identification of new genetic factors such as the C9ORF72 expansion and the development of human induced pluripotent stem cell technology (DeJesus-Hernandez et al, 2011;Renton et al, 2011;Richard and Maragakis, 2014;Takahashi and Yamanaka, 2006;Takahashi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Instead, the proposed mechanism of action was derived to be through expression and release of protective growth factors from the transplanted stem cells and their neuronal progeny (Xu et al, 2006). Subsequent studies showed an even greater therapeutic benefit when the human neural stem cells were targeted to not only the lumbar spinal cord, but also cervical segments as well (Xu et al, 2011). Additionally, experiments performed by Teng et al (2012) showed that transplanted human neural stem cells could attenuate the disease course of SOD1 G93A mice including improved motor performance, respiratory function, pathological measures, and increased survival .…”

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confidence: 99%

Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS)

Haidet-Phillips

Maragakis

2015

Brain Research

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ALS is a neurodegenerative disease with a prevalence rate of up to 7.4/100,000 and the overall risk of developing ALS over a lifetime is 1:400. Most patients die from respiratory failure following a course of progressive weakness. To date, only one traditional pharmaceutical agent-riluzole, has been shown to afford a benefit on survival but numerous pharmaceutical interventions have been studied in preclinical models of ALS without subsequent translation to patient efficacy. Despite the relative selectivity of motor neuron cell death, animal and tissue culture models of familial ALS suggest that non-neuronal cells significantly contribute to neuronal dysfunction and death. Early efforts to transplant stem cells had focused on motor neuron replacement. More practically for this aggressive neurodegenerative disease, recent studies, preclinical efforts, and early clinical trials have focused on the transplantation of neural stem cells, mesenchymal stem cells, or glial progenitors. Using transgenic mouse or rat models of ALS, a number of studies have shown neuroprotection through a variety of different mechanisms that have included neurotrophic factor secretion, glutamate transporter regulation, and modulation of neuroinflammation, among others. However, given that cell replacement could involve a number of biologically relevant factors, identifying the key pathway(s) that may contribute to neuroprotection remains a challenge. Nevertheless, given the abundant data supporting the interplay between non-neuronal cell types and motor neuron disease propagation, the replacement of disease-carrying host cells by normal cells may be sufficient to confer neuroprotection. Key preclinical issues that currently are being addressed include the most appropriate methods and routes for delivery of cells to disease-relevant regions of the neuraxis, cell survival and migration, and tracking the cells following transplantation. Central to the initial development of stem cell transplantation into patients with ALS is the demonstration that transplanted cells lack tumorigenicity and have the appropriate biodistribution to ensure the safety of ALS patients receiving these therapies. Here, we review preclinical and clinical studies focusing on the transplantation of neural and glial progenitor cells as a promising neuroprotective therapy for ALS. The rationale for stem cell transplantation for neuroprotection, proof-of-concept animal studies, and current challenges facing translation of these therapies to the clinic is presented. Lastly, we discuss advancements on the horizon including induced pluripotent stem cell technology and developments for cellular tracking and detection post-transplantation. With the safe completion of the first-in-human Phase I clinical trial for intraspinal stem cell transplantation for ALS in the United States, the time is ripe for stem cell therapies to be translated to the clinic and excitingly, evaluated for neuroprotection for ALS. This article is part of a Special Issue entitled SI: Neuroprotection.

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“…In order to support more muscle groups in SOD G93A rats, including muscles of hind-and forelimbs and respiratory, NSCs were injected into the ventral horn of both the lumbar and cervical spinal segments of presymptomatic animals. The dual treatment extended the survival of the rats by 17 days and delayed disease onset by 10 days compared to control animals, demonstrating the advantage of multiple injections [128]. A different study involving injection of NSCs to the lumbar ventral horn of presymptomatic SOD1…”

Section: Preclinical Studies Using Human Neural Stem Cellsmentioning

confidence: 94%

Astrocytes in Pathogenesis of ALS Disease and Potential Translation into Clinic

Izrael¹,

Guy²,

Itskovitz‐Eldor³

et al. 2018

Astrocyte - Physiology and Pathology

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Astrocytes are the major cell population in the central nervous system (CNS) and play pivotal role in CNS homeostasis and functionality. Malfunction of astrocytes were implicated in multiple neurodegenerative diseases and disorders, including amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), brain stroke, Parkinson's disease (PD), and Alzheimer disease (AD). These new insights led to the rationale that transplantation of healthy and functional human astrocytes could support survival of neurons and be of therapeutic value in treating neurodegenerative diseases. Here, we will mainly focus on the role of astrocytes in ALS disease, the major cell sources for generation of human astrocytes, or astrocyte like cells and show how multiple preclinical studies demonstrate the efficacy of these cells in animal models. In addition, we will cover immerging early stage clinical trials that are currently being conducted using human astrocytes or human astrocyte like cell population.

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Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats

Cited by 84 publications

References 35 publications

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

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

Neural and glial progenitor transplantation as a neuroprotective strategy for Amyotrophic Lateral Sclerosis (ALS)

Astrocytes in Pathogenesis of ALS Disease and Potential Translation into Clinic

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