Correction

This article refers to:

Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials

Article title: Stem cell treatments for amyotrophic lateral sclerosis: A critical overview of early phase trials

Authors: Goutman, SA, Savelieff, MG, Sakowski, SA, et al.

Journal: Expert Opinion on Investigational Drugs

Bibliometrics: Volume 28, Number 06, pages 525 - 543

DOI: http://dx.doi.org/10.1080/13543784.2019.1627324

When this article was first published, the alignment of the first row of Table 1 was incorrect. A word has also been replaced in the text and reference 7 has been realigned.

• (1)In section 4.2, second paragraph, the below sentence is corrected. The corrected word is given in bold font

The follow up study by the same investigators applied the same technique to 67 participants in an open-label fashion, with the aim of reporting safety [64].

• (2)Reference 7 is aligned properly and the correct reference is given below

• (3)The first row of the Table 1 in page 532 should be as given below

7. Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Jul;16(7):505–512.

Table 1. Summary of clinical stem cell trials in ALS.

Stem cell type	Clinical trial phase	Delivery method (target)	Dose	Patient eligibility	Patients (Controls)	Planned outcomes	Results	Reference(s)
PBSC	Pilot		G-CSF 2 µg/kg/day SC x 5 days	Not provided	13 (0)	Primary: ALSFRS Secondary: CMAP amplitude (muscle(s) not specified)	Reduction in slope of decline of ALSFRS-R and CMAP amplitude post procedure	Zhang (2009) [55]
	Pilot		G-CSF 5 µg/kg/day SC x 4 days repeated at months 0, 3, 6, 9	Age: 18–85 EEC: D, Pr Symptom duration: <6 years FVC: >50% FALS: Excluded Cognition: Normal	19 (20), but only those completing 6 months of study included in analysis Patients assessed at each month 0: 19 (20) 3: 17 (18) 6: 12 (16) 9: 9 (12)	Primary: ALSFRS-R Secondary: FVC, MMT megascore, CMAP megascore, NI, QoL; tracheostomy, death	No difference in clinical measures between treatment and placebo group No safety concerns G-CSF resulted in increased WBC count & circulating CD34+ cells	Nefussy (2010) [57]
	Phase I/II		G-CSF 5 µg/kg/day SC every 12 hours x 4 days at months 0, 3, 6, 9 with 125 mL 18% mannitol IV four times per day x 5 days starting on day 3 of G-CSF	Age: 40–65 EEC: D, Pr, Pr-LS Symptom duration: <12 months FVC: >80% FALS: Excluded Cognition: FTD excluded	24 (0) Patients assessed at each month 0: 24 3: 24 6: 21 9: 20	Primary: safety & tolerability, clinical progression, and changes in chemokine & cytokine levels	No safety concerns No change in disease progression ↑ WBC & CD34+ cells in blood ↓MCP-1 in CSF/serum ↓IL-17 in CSF ↑ IP-10 in serum	Tarella (2010) [58] Chio (2011) [59]
	Pilot	IV	G-CSF 300–600 µg/day SC x 5–6 days Leukapheresis for target of 2.0 × 10^6 CD34+ cells/kg	Not clearly specified	8 (0)	Not clearly specified	No safety concerns No change in disease progression No change in MRS NAA/Cr ratio	Cashman (2008) [60`]
	Pilot	Intrathecal	G-CSF administration followed by leukopheresis to isolate CD34+ cells	Case series	3 (0) Patient 1: 100 million cells via lumbar intrathecal catheter over 2 days Patient 2: 20 million cells over minutes intrathecal at L3/4 and cisterna magna Patient 3: 100 million cells intrathecal at C1/2 and lumbar region		Patient 1: 2 hour loss of sensation in lower limbs, subjective speech improvements Patient 2: no change in disease Patient 3: gain in leg and neck strength	Janson (2001) [62]
	Pilot	IV	Donor-mobilized CD34+ cells generated by G-CSF following total body radiation, fludarabine, and horse ATG Tacrolimus and methotrexate for GVHD prophylaxis	Age: 20–65 EEC: D FVC: >60% HLA-identical related donor	6 (matched historical controls)	Primary: Donor engraftment, clinical measures	Engraftment successful Cases of cutaneous and limited GVHD	Appel (2008) [61]
	Pilot	Intracortical	G-CSF 300 µg/daily SC x 3 days followed by isolation of CD133+ cells by leukapheresis	EEC: any FVC: any Severe bulbar involvement excluded	10 (13) Control patients were those that did not accept treatment but met inclusion criteria, or those that applied after study completed recruitment	Primary: survival rate Secondary: ALSFRS-R	No safety concerns. Improved survival in treatment group (disease duration 30.1 months in treatment group vs 14.3 in controls)	Martinez (2009) [63]
	Unspecified	Intracortical	G-CSF 300 µg/daily SC x 3 days followed by isolation of CD133+ cells by leukapheresis Bilateral injections into frontal motor cortex 3–4 cm from midline	EEC: any FVC: >30%	67 (0) Appears to have included patients previously reported in Martinez 2009 [63]	Primary: Safety (not clearly specified)	2 subject deaths in post-operative period (respiratory failure, MI/SDH); otherwise procedure was well tolerated	Martinez (2012) [64]
BM-MSCs	Phase I/II	Intrathecal (10 patients) Intrathecal + Intravenous (9 patients)		EEC: D Age: 25–65 At least 5-point decline in ALSFRS in one year	19 (0)	Primary: Safety analysis	No safety concerns	Karussis (2010) [40]
	Pilot	Intrathecal	Intrathecal administration at L2/3 or L3/4	EED: D, Pr, Pr-LS Age: >18	10 (0)	Primary: ALSFRS-R at day 90, 180, 270, 365 Secondary: ALSFRS-R subscores, time to 4-point worsening, survival	Trend towards stabilization of ALSFRS-R (individual patient characteristics are not reported such as disease duration which could impact interpretation) No safety concerns	Prabhakar (2012) [65]
	Phase I	Intrathecal (8 patients) Intravenous (6 patients)	2 x 10^6 cells/kg	EEC: D ALSFRS ≥ 24 FVC ≥ 40%	14 (0)	Primary: Safety Secondary: ALSFRS, FVC, MRI	1 subject death; 1 lost to follow up per group No safety concerns	Nabavi (2019) [66]
	Phase I/IIa	Intrathecal	15 ± 4.5 x 10^6	EEC: D Age: 18–65 Riluzole naïve or stable dose for 2 mo Life expectancy ≥ 2 yr	26 (0)	Primary: Safety Secondary: ALSFRS, FVC, weakness scales	No safety concerns reduction in ALSFRS-R decline at 3 and up to 6 mo; FVC stable of above 70% for 9 mo in 80% subjects; stable weakness scales at 3 mo in 75% patients	Syokva (2017) [67]
	Phase I	Intrathecal	7.89 ± 5.77 x 10^6 Lin- cells administered at L3/4 or L4/5	EEC: D Age: <65 Survival prognosis ≥12 mo	12 (0)	Primary: Safety Secondary: CSF/plasma microRNAs, Norris scale, ALSFRS	No safety concerns Decreased inflammatory proteins Effects on progression correlated with higher Lin- doses	Sobus (2017) [68]
	Phase I	Intrathecal	1 x 10^6 cells/kg x 2 injections 26 days apart	EED: D, Pr Age: 25–75 ALSFRS-R 31–46 Stable riluzole dose >3 mo Disease duration ≤5 yr FVC > 40%	8 enrolled but only 7 completed treatment (0)	Primary: Safety Secondary: ALSFRS-R, Appel score, FVC	1 subject death before treatment; no acceleration in ALSFRS-R decline rates No safety concerns	Oh (2015) [69]
	Phase II	Intrathecal	1 x 10^6 cells/kg x 2 injections 26 days apart	EED: D, Pr Age: 25–75 ALSFRS-R 31–46 Stable riluzole dose >3 mo Disease duration ≤5 yr FVC > 40%	33 (31)	Primary: Safety, ALSFRS-R Secondary: CSF biomarkers, survival	No safety concerns Reduced ALSFRS-R rate changes from baseline Reduced pro-inflammatory and increased anti-inflammatory cytokines; TGF-β1 inversely correlated with MCP-1 in good responders No survival difference	Oh (2018) [70]
	Phase III	Intrathecal	3 bimonthly injections of MSCs induced to secrete NTFs or placebo	EEC: D, Pr, Pr-LS, Po Age: 18–60, ALSFRS-R > 25, SVC > 65%	100 estimated (100)	Primary: Safety, efficacy (ALSFRS-R) Secondary: CSF/serum neurotrophic factors, inflammatory factors, cytokines	Study in progress, results not yet reported	Clinical Trial NCT03280056
	Phase II	Intramuscular, Intrathecal	MSCs induced to secrete NTFs	EEC: D, Pr, Pr-LS, Po Age: 18–75 Disease duration <24 months but > 12 months ALSFRS-R > 30 SVC > 65%	48 participants in total	Primary: Safety Secondary: change in ALSFRS-R, change in SVC	Study in progress, results not yet reported	Clinical Trial NCT02017912
	Phase I/II, Phase IIa	Intramuscular or Intrathecal (Phase 1/2) Intramuscular+Intrathecal (Phase 2a)	MSCs induced to secrete NTFs 24 x 10^6 cells intramuscular or 1 × 10^6 cells/kg intrathecal Intramuscular/Intrathecal Low: 24x10^6/1x10^6/kg Mid: 36x10^6/1.5x10^6/kg High: 48x10^6/2x10^6/kg	EEC: D, Pr Disease duration <24 months Phase 1/2: ALSFRS-R > 30 for intramuscular; between 15–30 and FVC >50% intrathecal Phase 2a: ALSFRS-R > 30; FVC > 50%	26 (0) 6 patients: Intramuscular 6 patients, Intrathecal 14 patients: Intramuscular+Intrathecal	Primary: Safety Secondary: ALSFRS-R, FVC	No safety concerns Progression declines in ALSFRS-R and FVC reduced in intrathecal and in intramuscular+ intrathecal groups	Petrou (2016) [82]
	Case report	Intraventricular	1 x 10^6 cells/kg	Case report of 63-year-old with definite ALS by EEC	1 (0)	Authors state ALS was too advanced to assess efficacy	No safety concerns	Baek (2012) [77]
	Phase I	Intraspinal	Cells injected into thoracic cord (central part of spinal cord) 1 mm apart in 3 rows spaced by 3 mm	EEC: D Ages: 21–75 Disease duration: 6–96 months Mild to severe functional impairment at spinal level No or mild bulbar involvement No respiratory failure	7 (0) (+ 2 patients under compassionate use)	Primary: ALSFRS, Norris score, FVC every 3 months following 6-month lead in period	4 patients showed a reduction in the ALSFRS-R and FVC decline No safety concerns	Mazzini (2006) [72] Mazzini (2008) [38] Mazzini (2012) [73]
	Phase I	Intraspinal	Same methods as 2006 study [72]	EEC: D, Pr Ages: 20–65 Disease Duration: <3 years FVC: >50% FALS: excluded Onset: spinal	10 (0)	Primary: ALSFRS, MRC, respiratory assessment, MUNE, neurophysiological index, MRI, DTI, safety	No change in the rate of decline of clinical measures No safety concerns	Mazzini (2010) [71] Mazzini (2012) [`73]
	Phase I	Intraspinal	T3/4 injections 1–2.5 mm from midline at depth of 6 mm	EEC: D Ages: 20–65 Disease duration: 6–36 months FVC: >50% Onset: Spinal	11 (0)	Primary: Safety Secondary: FVC, ALSRFS, MRC, Norris scale	No safety concerns No changes in disease progression	Blanquer (2010) [34] Blanquer (2012) [74]
	Phase II	Intraspinal	C1/2 laminectomy and multiple injections at these levels	Disease duration: >6 months FALS: excluded Rapid decline, FVC in terminal period (on mechanical ventilator or unable to speak)	13 (0)	Primary: not specified	No safety concerns Authors report 9 of 13 patients improved post procedure (no clear criteria for assessment)	Deda (2009) [76]
	Pilot	Intraarterial	T-cell vaccination every 28 days for 10 doses Bone marrow harvest, following purification, one aliquot given to patient on same day ‘by selective intralesion infusion into the feeding artery’ MSCs differentiated into NSCs and given intraarterial	Disease duration 3–5 years	7 (0), only 5 completed full regimen	Primary: ALSFRS-R	No safety concerns Results not well reported, no apparent change in disease progression	Moviglia (2012) [81]
Adipose derived MSCs	Phase I	Intrathecal	Dose escalation over 5 groups receiving between 1 × 10^7 cells in 1 dose up to 1 × 10^8 cells in 2 monthly doses	EEC: D FVC >65% Disease duration between 1–2 years	27 (0)	Primary: Safety Secondary: ALSFRS-R, MRI, CSF/blood	Positive safety profile Side effects related to increased protein and nucleated cell levels in CSF and thickened lumbosacral nerve roots 4 subject deaths; autopsy revealed no tumors Efficacy testing in progress (see NCT03268603)	Staff (2016) [83]
	Phase II	Intrathecal	1 x 10^8 cells every 3 mo for 12 mo Dose reductions may occur for subsequent doses per Dose Modification Rules	EEC: any Age: ≥18 Disease duration <2 y Stable or no riluzole ≥ 30 d	60 estimated (0)	Primary: Safety Secondary: ALSFRS-R	Study in progress, results not yet reported	Clinical Trial NCT03268603
OECs	Pilot	Intracortical	OECs extracted from human fetal olfactory bulb tissue 2 million OECs injected into bilateral corona radiata	EEC: D, Pr Age: 20–70 ALSFRS ≥ 15	15 (20) Controls not randomized, rather first 15 patients served as cases and next 20 as controls; no formal matching No patients share nationality of the study (China)	Primary: ALSFRS at four months provided by patient, caregiver, and family member	Rate of decline between month 3 and 4 was slower for the treatment group compared to control Authors do not report presence/absence of adverse events, however, additional safety and efficacy outcomes reported in references [84–86](see text)	Huang (2008) [49]
	Unspecified	Intracortical, Intraspinal	Intraspinal injections not standardized, reported to occur at impaired segments Authors suggest all patients received intraspinal injections, although the 2007 report suggest some patients only received intracortical injections	EEC; D, Pr Age: >18	507 (0) Intracortical only: 35 patients second injection; 5 patients 3 injections; 1 patient 4 injections; 1 patient 5 injections	ALSFRS, Norris scale, video recordings of patients, EMG, PFT	Authors report improved ALSFRS-R and respiratory measures after each treatment, although a progressive decline in ALSFRS-R continued	Chen (2007) [35] Chen (2012) [50]
NPCs	Phase I	Intraspinal	Dose escalation Patients immunosuppressed with basiliximab mycophenolate mofetil, and tacrolimus and received tapering steroid dose following injections	Disease severity changed during trial to enroll less severely affected patients in later groups	15 (0)	Primary: Safety	No safety concerns Possible slowing of disease progression in patients without bulbar symptoms early in disease course, however, number of subjects fulfilling this criteria is small	Riley (2012) [87] Glass (2012) [88] Riley (2014) [89] Tadesse (2014) [91] Feldman (2014) [90]
	Phase II	Intraspinal	Dose escalation Same immunosuppression regimen as phase I	EEC: D, Pr, Pr-LS Age: >18 FVC: >60% seated, >50% supine SALS or FALS	15 (0)	Primary: Safety Secondary: attenuation of motor function loss, maintenance of respiratory capacity, stabilization of ALSFRS-R, reduction of spasticity/rigidity, graft survival	No safety concerns 1 post-op deterioration in neurological function, 1 central pain syndrome No effect on progression rates versus historical controls Improved functional and survival outcomes using ALS/SURV measure relative to historical controls after longer-term follow up	Glass (2016) [92] Goutman (2018) [93]
	Phase I	Intraspinal	3 unilateral lumbar injections (3 patients) 3 + 3 bilateral lumbar injections (3 patients) NPC source from natural miscarriages	EEC: D, Pr Age: 20–75 Non-ambulatory Evidence of progression in last 6 mo No apnea; O2 sat ≥ 90% FVC >60%	6 (0)	Primary: Safety Secondary: ALSFRS-R, FVC	No safety concerns No increase in disease progression rates through 18 mo	Mazinni (2015) [94]
	Phase I	Intraspinal	NPCs modified to express GDNF Two doses delivered unilaterally to the lumbar region	EEC: D, Pr, Pr-LS Disease duration ≤36 mo Lower extremity weakness FVC >60% Age: ≥18 Stable or no riluzole ≥30 d	18 estimated (0)	Primary: Safety Secondary: CMAP, ATLIS, quantitative muscle MRI, EIM; CSF GDNF levels	Study in progress, results not yet reported	Clinical trial NCT02943850

ALSFRS, ALS Functional Rating Scale (non-revised, original); ALSFRS-R, ALS Functional Rating Scale Revised; ATLIS, Accurate Test of Limb Isometric Strength; CMAP, compound muscle action potential; Cr, creatine; D, Definite; DTI, diffusion tensor imaging; EEC, El Escorial Criteria; EIM, electrical impedance myography; EMG, electromyography; FALS, familial ALS; FVC, forced vital capacity; GDNF, glial cell-derived neurotrophic factor; HLA, human leukocyte antigen; IV, intravenous; Lin-, lineage negative; MCP-1, monocyte chemoattractant protein-1; MI/SDH, myocardial infarction with subdural hematoma; MMT, manual muscle strength; MRC, Medical Research Council; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MSC, mesenchymal stem cells; MUNE, motor unit number estimation; NAA, N-acetylasparate; NI, neurophysiological index (NI = CMAP amplitude x F-wave persistence/distal motor latency in ulnar nerves); NPC, neural progenitor cell; NSC, neural stem cells; NTF, neurotrophic factors; OECs, olfactory ensheathing cells; PFT, pulmonary function test; Po, Possible; Pr, Probable; Pr-LS, Probable-Laboratory Supported; QoL, quality of life; SALS, sporadic ALS; SVC, slow vital capacity; TGF-β1, transforming growth factor beta 1.

Reprinted and updated with permission from Springer Nature, Neurotherapeutics, Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis. SA Goutman, KS Chen, EL Feldman, 12(2), 2015.