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

Goutman, Stephen A.; Chen, Kevin S.; Feldman, Eva L.

doi:10.1007/s13311-015-0339-9

Cited by 20 publications

(23 citation statements)

References 129 publications

(116 reference statements)

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“…The complex pathogenesis and limited efficacy of disease‐modifying therapies predicates an urgent need for novel treatment strategies. Recent studies examining cellular transplantation for neurological disorders2 prompted interest in cell‐based therapies for ALS, and several cell types and delivery strategies are being evaluated in preclinical and translational ALS studies 3, 4…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies examining cellular transplantation for neurological disorders 2 prompted interest in cell-based therapies for ALS, and several cell types and delivery strategies are being evaluated in preclinical and translational ALS studies. 3,4 Human spinal cord-derived neural stem cell (HSSC) intraspinal transplantation as a therapeutic approach has progressed to clinical trials in ALS patients. This approach is supported by in vitro and in vivo preclinical studies [5][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: 99%

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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: 99%

Section: Introductionmentioning

confidence: 99%

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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“…The next criterion, concerning the delivery techniques for different stem cell types in ALS therapy, includes intra‐thecal, intra‐spinal, intra‐ventricular, intra‐muscular, and intra‐arterial routes of administration. Ultimately, the last condition refers to the integrity of stem cells, which must be clinically quantifiable (Goutman et al, 2015). This results in the need to track grafted cells from the moment of their transplantation until they reach the host environment.…”

Section: Clinical Advances In Stem Cell Therapies For Alsmentioning

confidence: 99%

“…This cellular imaging technique, combined with contrast agents, has been widely used in in vitro studies, where grafted cells with efficient labeling did not exhibit impaired survival, proliferation, self‐renewal or multipotency (Neri et al, 2008). Cell integrity also depends on the progression of the disease and changes in functional status in ALS patients, which are measured using the Revised ALS Functional Rating Scale (ALSFRS‐R) (Goutman et al, 2015). Additionally taken into account are also the estimated respiratory parameters and lifespan, as well as the records of a given number of assessed improvements in health as compared to control treatments.…”

Section: Clinical Advances In Stem Cell Therapies For Alsmentioning

confidence: 99%

Stem cells for ALS: An overview of possible therapeutic approaches

Czarzasta

Habich

Siwek

et al. 2017

Intl J of Devlp Neuroscience

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Amyotrophic lateral sclerosis (ALS) is an unusual, fatal, neurodegenerative disorder leading to the loss of motor neurons. After diagnosis, the average lifespan ranges from 3 to 5 years, and death usually results from respiratory failure. Although the pathogenesis of ALS remains unclear, multiple factors are thought to contribute to the progression of ALS, such as network interactions between genes, environmental exposure, impaired molecular pathways and many others. The neuroprotective properties of neural stem cells (NSCs) and the paracrine signaling of mesenchymal stem cells (MSCs) have been examined in multiple pre-clinical trials of ALS with promising results. The data from these initial trials indicate a reduction in the rate of disease progression. The mechanism through which stem cells achieve this reduction is of major interest. Here, we review the to-date pre-clinical and clinical therapeutic approaches employing stem cells, and discuss the most promising ones.

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“…Linga Reddy and Timothy Miller [13] that details the recent advances in RNA-based therapeutics for ALS and emphasizes the current progress in the preclinical and early clinical applications of antisense oligonucleotides and small interfering RNAs. The final paper, by our research group, then reviews the current progress in the development and application of stem cell-based therapies in ALS [14]. Briefly, we present preclinical data examining the therapeutic utility of various stem cell types and an overview of the paradigms that have progressed to early clinical trials; we include a brief update on the recent progress of our own clinical trial examining intraspinal transplantation of neural progenitor cells in patients with ALS.…”

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confidence: 99%

The Spectrum of Motor Neuron Diseases: From Childhood Spinal Muscular Atrophy to Adult Amyotrophic Lateral Sclerosis

Sakowski

Feldman

2015

Neurotherapeutics

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Since the topic of motor neuron diseases was last covered in Neurotherapeutics in 2008, increasing insight into genetic causes and underlying disease mechanisms has fueled several advances that have paved the way for new therapeutic strategies that are currently in development or being tested in clinical trials. In this special issue, we present reviews by leading investigators in the field that detail these advances for spinal muscular atrophy (SMA), an inherited neuromuscular disease associated with motor neuron degeneration and muscle atrophy that presents early in life, and amyotrophic lateral sclerosis (ALS), a fatal adult-onset neuromuscular disease also characterized by loss of motor neurons. The papers are divided into 4 main sections that cover 1) SMA advances, 2) ALS challenges and recent biological advances, 3) ALS clinical trial design considerations and outcome measures, and 4) emerging ALS treatments. Together, these articles offer a timely and comprehensive look into the recent research advances, current clinical considerations, and therapeutic prospects currently in development or being tested for motor neuron diseases.The issue begins with 2 papers focused on SMA. In the first article, Drs. Michelle Farrar and Matthew Kiernan [1] provide a detailed overview of the genetic basis of SMA forms and variants and present common pathophysiological mechanisms, including discussion of the function of the survival motor neuron protein. They then discuss considerations for therapeutic development and testing before reviewing potential molecular biomarkers for outcome assessments and trial design. Next, Drs. Constantin d'Ydewalle and Charlotte Sumner [2] present an eloquent synopsis of promising SMA treatments currently in advanced stages of development, a discussion that is prefaced by an overview of the available in vivo mouse SMA models. The treatment strategies include some originally designed for applications in ALS, approaches to induce survival motor neuron, and new treatment paradigms harnessing epigenetic targets, antisense oligonucleotides, and gene therapy approaches. Notably, both articles also discuss important issues that remain to be addressed for current progress, such as how well preclinical models recapitulate the human phenotype, how to factor in disease heterogeneity and identify and define potential therapeutic windows, and how to best analyze effects on disease progression. We believe the recent novel insights and current advances bode well for continued progress and the identification of much needed treatment options in SMA.The second section of the issue begins with a review by Drs. Jeffrey Rosenfeld and Michael Strong [3], which specifies the current challenges underlying therapeutic development that accompany the recent expansions in our understanding of the complex, multifaceted nature of ALS. Briefly, establishing firm diagnostic and prognostic criteria, determining what role frontotemporal dysfunction plays in the classification of ALS, identifying an accepted biomarker, determi...

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

Cited by 20 publications

References 129 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

Stem cells for ALS: An overview of possible therapeutic approaches

The Spectrum of Motor Neuron Diseases: From Childhood Spinal Muscular Atrophy to Adult Amyotrophic Lateral Sclerosis

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