Table 2.

Summary of clinical stem cell trials in amyotrophic lateral sclerosis

Stem cell type	Delivery method (target)	Dose	Patient eligibility	Patients (controls)	Planned outcomes	Results	Reference(s)
PBSC		G-CSF 2 μg/kg/day SC × 5 days	Not provided	13 (0)	Primary: ALSFRS-R Secondary: CMAP amplitude (muscle(s) not specified)	Reduction in slope of decline of ALSFRS-R and CMAP amplitude postprocedure	Zhang (2009) [61]
		G-CSF 5 μg/kg/day SC × 4 days repeated at months 0, 3, 6, 9	Age: 18–85 years 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) [62]
		G-CSF 5 μg/kg/day SC every 12 h × 4 days at months 0, 3, 6, 9 with 125 ml 18 % mannitol IV 4 times per day × 5 days starting on day 3 of G-CSF	Age: 40–65 years 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 and tolerability, clinical progression, and changes in chemokine and 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) [63] Chio (2011) [64]
	IV	G-CSF 300–600 μg/day SC × 5–6 days Leukapheresis for target of 2.0 × 106 CD34+ cells/kg	Not clearly specified	8 (0)	Not clearly specified	No safety concerns No chance in disease progression No change in MRS NAA/Cr ratio	Cashman (2008) [65]
	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 h 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) [66]
	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 years 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) [67]
	Intracortical	G-CSF 300 μg/daily SC × 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) [68]
	Intracortical	G-CSF 300 μg/daily SC × 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 [68]	Primary: Safety (not clearly specified)	2 subject deaths in postoperative period (respiratory failure, MI/SDH); otherwise procedure was well tolerated	Martinez (2012) [69]
Bone marrow derived MSCs	Intrathecal (10 patients) Intrathecal + Intravenous (9 patients)		EEC: D Age: 25–65 years At least 5 point decline in ALSFRS in 1 year	19 (0)	Primary: Safety analysis	No safety concerns	Karussis (2010) [70]
	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) [71]
	Intramuscular, Intrathecal	MSCs induced to secrete NTFs	EEC: D, Pr, Pr-LS, Po Age: 18–75 years Disease duration <24 months ALSFRS-R > 30 SVC > 65 %	48 estimated (0)	Primary: Safety Secondary: change in ALSFRS-R, change in SVC	Study in process, results not yet reported	Clinical Trial
	Intraventricular	1 × 107 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) [72]
	Intraspinal	Cells injected into thoracic cord (central part of spinal cord) 1 mm apart in 3 rows spaced by 3 mm	EEC: D Age: 21–75 years 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-R, 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) [73] Mazzini (2008) [74] Mazzini (2012) [75]
	Intraspinal	Same methods as 2006 study [73]	EEC: D, Pr Age: 20–65 years Disease Duration: <3 years FVC: >50 % FALS: excluded Onset: spinal	10 (0)	Primary: ALSFRS-R, MRC, respiratory assessment, MUNE, neurophysiological index, MRI, DTI, safety	No change in the rate of decline of clinical measures No safety concerns	Mazzini (2010) [76] Mazzini (2012) [75]
	Intraspinal	T3-4 injections 1–2.5 mm from midline at depth of 6 mm	EEC: D Age: 20–65 years Disease duration: 6–36 months FVC: >50 % Onset: Spinal	11 (0)	Primary: Safety Secondary: FVC, ALSRFS-R, MRC, Norris scale	No safety concerns No changes in disease progression	Blanquer (2010) [77] Blanquer (2012) [78]
	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 7/13 patients improved postprocedure (no clear criteria for assessment)	Deda (2009) [79]
	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 intra-arterial	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) [80]
OECs	Intracortical	OECs extracted from human fetal olfactory bulb tissue 2 million OECs injected into bilateral corona radiata	EEC: D, Pr Age: 20–70 years ALSFRS-R ≥ 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-R at 4 months provided by patient, caregiver, and family member	Rate of decline between months 3 and 4 was slower for the treatment group compared with control Authors do not report presence/absence of adverse events; however, additional safety and efficacy outcomes reported in references [81–83] (see text)	Huang (2008) [84]
	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 years	507 (0) Intracortical only: 35 patients second injection; 5 patients 3 injections; 1 patient 4 injections; 1 patient 5 injections	ALSFRS-R, 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) [85] Chen (2012) [86]
NPCs	Intraspinal (phase I)	Dose escalation, see Table 3 for details 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) [90] Feldman (2014) [91]
	Intraspinal (phase II)	Dose escalation, see Table 3 for details Same immunosuppression regimen as phase I	EEC: D, Pr, Pr-LS Age: >18 years 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	Study in process, results not yet reported	Clinical trial NCT01730716

ALSRFS-R ALS Functional Rating Scale Revised, CMAP compound muscle action potential, Cr creatine, D Definite, EEC El Escorial Criteria, FALS familial ALS, FVC forced vital capacity, HLA human leukocyte antigen, IV intravenous, MMT manual muscle strength; MRS magnetic resonance spectroscopy, MSC mesenchymal stromal cells, NAA N-acetylasparate, NI neurophysiolocal index (NI = CMAP amplitude × F-wave persistence / distal motor latency in ulnar nerves), NPC neural progenitor cell, NSC neural stem cells, NTF neurotrophic factors, OECs olfactory ensheathing cells, Po Possible, Pr Probable, Pr-LS Probable-Laboratory Supported, QoL quality of life, SALS sporadic ALS, SVC slow vital capacity; PBSC peripheral blood stem cell; G-CSF granulocyte colony stimulating factor; SC stem cell; WBC white blood cell; FTD frontotemporal dementia; MCP-1 monocyte chemoattractant protein-1; CSF cerebrospinal fluid; IL-17 interleukin-17; IP-10 interferon-induced protein-10; ATG ATGAM; GVHD graft versus host disease; MI myocardial infarction; SDH subdural hematoma; MUNE motor unit number estimation; MRI magnetic resonance imaging; DTI diffusion tensor imaging; MRC Medical Research Council; EMG electromyographt; PFT pulmonary function test