Original Article

Safety, Feasibility of Intravenous and Intrathecal Injection of

Autologous Bone Marrow Derived Mesenchymal Stromal Cells
in Patients with Amyotrophic Lateral Sclerosis: An Open
Label Phase I Clinical Trial

Seyed Massood Nabavi, M.D.1#, Leila Arab, M.D.2#, Neda Jarooghi, M.Sc.1, Tina Bolurieh, M.Sc.1, Fatemeh
Abbasi, M.Sc.1, Soura Mardpour, Ph.D.1, Vajihe Azimyian, Ph.D.1, Fatemeh Moeininia, M.D.1, Saman
Maroufizadeh, M.Sc.3, Leila Sanjari, M.D.4, Seyedeh Esmat Hosseini, M.Sc.5,
Nasser Aghdami, M.D., Ph.D.1*
1. Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR,
Tehran, Iran
2. Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
3. Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive
Medicine, ACECR, Tehran, Iran
4. Intensive Care Unit, Mostafa Khomeini Hospital, Tehran, Iran
5. Student Research Committee, School of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran

#The first two authors equally contributed to this work.

*Corresponding Address: P.O.Box: 16635-148, Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell
Biology and Technology, ACECR, Tehran, Iran
Email: Nasser.aghdami@royaninstitute.org

Received: 6/Jul/2017, Accepted: 28/Dec/2018

Abstract
Objective: Amyotrophic lateral sclerosis (ALS) is the most severe disorder within the spectrum of motor neuron diseases
(MND) that has no effective treatment and a progressively fatal outcome. We have conducted two clinical trials to assess the
safety and feasibility of intravenous (IV) and intrathecal (IT) injections of bone marrow derived mesenchymal stromal cells
(BM-MSCs) in patients with ALS.
Materials and Methods: This is an interventional/experimental study. We enrolled 14 patients that met the following inclusion
criteria: definitive diagnosis of sporadic ALS, ALS Functional Rating Scale (ALS-FRS) ≥24, and ≥40% predicted forced vital
capacity (FVC). All patients underwent bone marrow (BM) aspiration to obtain an adequate sample for cell isolation and
culture. Patients in group 1 (n=6) received an IV and patients in group 2 (n=8) received an IT injection of the cell suspension. All
patients in both groups were followed at 24 hours and 2, 4, 6, and 12 months after the injection with ALS-FRS, FVC, laboratory
tests, check list of side effects and brain/spinal cord magnetic resonance imaging (MRI). In each group, one patient was lost to
follow up one month after cell injection and one patient from IV group died due to severe respiratory insufficiency and infection.
Results: During the follow up there were no reports of adverse events in terms of clinical and laboratory assessments.
In MRI, there was not any new abnormal finding. The ALS-FRS score and FVC percentage significantly reduced in all
patients from both groups.
Conclusion: This study has shown that IV and IT transplantation of BM-derived stromal cells is safe and feasible (Registration
numbers: NCT01759797 and NCT01771640).

Keywords: Amyotrophic Lateral Sclerosis, Bone Marrow, Intrathecal, Intravenous, Mesenchymal Stromal Cell
Cell Journal(Yakhteh), Vol 20, No 4, Jan-Mar (Winter) 2019, Pages: 592-598

Citation: Nabavi SM, Arab L, Jarooghi N, Bolurieh T, Abbasi F, Mardpour S, Azimyian V, Moeininia F, Maroufizadeh S, Sanjari L, Hosseini SE, Aghdami N.
Safety, feasibility of intravenous and intrathecal injection of autologous bone marrow derived mesenchymal stromal cells in patients with amyotrophic lateral
sclerosis: an open label phase I clinical trial. Cell J. 2019; 20(4): 592-598. doi: 10.22074/cellj.2019.5370.

Introduction
blood stem cells (PBSC) (7, 8), mesenchymal stromal
Amyotrophic lateral sclerosis (ALS) is one of the cells (MSCs) (9-15), olfactory ensheathing cells (OEC)
most damaging motor neuron diseases (MNDs) that (16) and fetal neural stem cells (NSC) (17-19). One of
has a worldwide incidence of 2-3 per 100,000 (1). Until the most considerable stem cells are MSCs which use
now, there is no effective medication to halt disease several mechanisms to correct ALS impairments such
progression or provide a cure. Available treatments are as rich trophic factor secretion, immunomodulation
limited to pharmaceuticals (riluzole) (2), physical and by increased expressions of interlukin-10 (IL-10) and
speech therapy (3), nutrition, and respiratory support Transforming growth factor beta-1 (TGF-β1) (20),
(4, 5). In the last decade, stem cell transplantation has gene delivery or replacing lost cells (21). Therefore,
been considered as a promising therapeutic option MSCs could induce neuroprotective effects on
for these patients (6). Recent studies demonstrated glutamate excitoxicity by inhibiting the expression
the safety and efficacy of different types of stem cell of N-methyl-D-aspartate (NMDA) receptor and
transplantations in ALS patients such as peripheral controlling glutamate related Ca2+ influx (22).
Cell J, Vol 20, No 4, Jan-Mar (Winter) 2019 592
MSC for ALS

GABAergic transmission increases in neurons co- of MSCs in ALS patients. As a secondary objective,
cultured with MSCs and can induce neural repair (23). we compared the effects of each route of injection on
Therefore, MSCs have the potential to improve neural prevention of disease progression.
function in a damaged area of the central nervous
system (24-26). In an animal model of ALS, it has Materials and Methods
been shown that MSC transplantation in SOD1/G93A
mice restored motor neurons, prolonged life span, and This is an interventional/experimental study. We
improved motor function by the secretion of growth conducted these two clinical trials as phase 1 open
factors, immunomodulatory effects, and reductions of label clinical studies at Royan Institute in collaboration
oxidative stress (26) . In previous studies, stem cell with the Neurology Department of Mostafa Khomeini
transplantation was performed via different routes in Hospital. After study approval from the Royan Institute
ALS patients such as intrathecal (IT) (9, 20), intraspinal Ethics Research Committee (No. EC/91/1097), eligible
(27, 28), intravenous (IV) (7, 9), intraventricular (11), patients signed the informed consent and enrolled in the
intracortical (29), and intra-arterial (30) injections. study. These studies were registered at the NIH clinical
However, the preferred route of administration has yet trial site (www.clinicaltrials.gov) with identification
to be determined in ALS. Therefore, we initiated this numbers NCT01759797 and NCT01771640. Figure 1
study to evaluate the safety of IV and IT injections shows the study flowchart.

Fig.1: Study flow diagram.

Cell J, Vol 20, No 4, Jan-Mar (Winter) 2019 593

 Nabavi et al.

Patients 37˚C. All non-adherent cells were removed by changing

the culture medium after 3-4 days. This process was
A total of 14 male and female patients with definitive
repeated every 3 days. After 1 to 2 passages, the 90%
diagnosis of sporadic ALS, aged 24-60 years, enrolled
confluent MSCs were harvested by the application of
in the studies. All patients had definite diagnosis of ALS
0.25% trypsin in 0.1% Ethylenediaminetetraacetic acid
due to EL Escorial criteria (31) and more than 6 months
(EDTA). Cell viability was evaluated by trypan blue
of evolution of disease, an ALS Functional Rating Scale
staining as well as the NucleoCounter® system. Next, we
(ALS-FRS) score ≥24, and ≥40% predicted forced vital
suspended MSCs (2×106 cells/kg) in 5 ml of 0.9% sodium
capacity (FVC). All patients were treated by the only
chloride that contained 2% human serum albumin.
approved drug for ALS, riluzole, at a dose of 100 mg,
twice per day. Exclusion criteria were any concomitant
Flow cytometry
neurological, psychiatric or systemic diseases or use of any
corticosteroids, immunoglobulin, or immunosuppressant Cell surface marker expressions were assessed by
treatments during 6 months before enrollment. Patients’ flow cytometry. The characterization panel consisted
descriptive characteristics are listed in Table 1. of monoclonal antibodies for mesenchymal lineages
markers CD90-FITC (BD, PharmingenTM, USA), CD105-
Bone marrow derived mesenchymal stromal cells PE (Endoglin, BD PharmingenTM, USA), CD73-PE (BD
production PharmingenTM, USA), CD44-FITC (BD PharmingenTM,
USA), CD45 FITC-CD34 PE (BD PharmingenTM, USA)
Each patient underwent bone marrow aspiration from
and CD11b (BD PharmingenTM, USA), along with the
the posterior superior iliac crest while in the right or left
following isotype controls, MultiMixTM FITC Mouse
lateral positions under local anesthesia. The MSCs were
IgG1, PE-Mouse IgG1 (Dako, Denmark), FITC-Mouse
prepared from bone marrow sample (100 ml) according to
IgG2b (Millipore, USA), and PE-conjugated Mouse
current good manufacturing practice (cGMP).
IgG1k (BD PharmingenTM, USA). Cells were fixed with
Mononuclear cells (MNCs) were isolated from the BM 4% paraformaldehyde and immunophenotyping analysis
samples by density gradient with a Ficoll Paque open was performed by the BD FACS Calibur flow cytometry
system (Lymphodex, Inno-Train, Germany). Next, the system (BD Biosciences, USA).
MNC layer was isolated and washed in PBS buffer (Milteny
Biotech GmbH, Germany). Cell counts and viability were Cell transplantation
assessed with trypan blue staining and confirmed by a
NucleoCounter® system (ChemoMetec, Denmark). MNCs Patients were scheduled to receive either the IV or IT
(1×106/cm2) were placed in Millicell® HY T-600 culture injections of the prepared MSC suspension (2×106 cells/
flasks (Merk, Germany) and cultured under standard kg) (Table 2). After cell transplantation, each patient
conditions in 1X MEM alpha medium (Gibco, Germany) remained under close observation for 24 hours. Then, we
and fetal bovine serum (FBS, Gibco, Germany). Flasks followed them with regular assessments at 24 hours, and
were incubated under defined conditions of 5% CO2 and 2, 4, 6, and 12 months after the cell administration.

Table 1: Patients’ characteristics

Patient Age (Y) Sex ALS onset ALS duration (months PEG (months Tracheostomy (months from
from diagnosis) from injection) injection)
1 50 Male Limb 18 8 10
2 59 Male Bulbar 6 N/A N/A
3 60 Female Limb 18 N/A N/A
4 35 Female Limb 6 N/A N/A
5 34 Female Limb 10 N/A N/A
6 57 Female Limb 12 N/A N/A
7 51 Male Bulbar 6 N/A N/A
8 54 Male Bulbar 6 N/A N/A
9 53 Male Bulbar 30 N/A N/A
10 57 Female Limb 48 N/A N/A
11 31 Male Limb 12 N/A N/A
12 42 Male Limb 9 N/A N/A
13 39 Male Limb 24 4 4
14 24 Male Limb 24 N/A N/A

N/A; Not applicable, ALS; Amyotrophic lateral sclerosis, and PEG; Percutaneous endoscopic gastrostomy.

Cell J, Vol 20, No 4, Jan-Mar (Winter) 2019 594

MSC for ALS

Table 2: Cell information

Patient Route of injection Cell count (×106) Cell viability (%) Bacteriology Mycoplasma Endotoxin Karyotype
level (EU/ml)
1 IV 95 100 NC NC <0.125 46XY
2 IV 125 98 NC NC <0.125 46XY
3 IV 75 92.80 NC NC <0.125 46XX
4 IV 111 94 NC NC <0.125 46XX
5 IV 89 93 NC NC <0.125 46XX
7 IT 113 99.50 NC NC <0.125 46XY
8 IT 102 94 NC NC <0.125 46XY
9 IT 100 98 NC NC <0.125 46XY
10 IT 135 97 NC NC <0.125 46XX
11 IT 140 96 NC NC <0.125 46XY
12 IT 100 96 NC NC <0.125 46XY
13 IT 120 98 NC NC <0.125 46XY
IV; Intravenous, IT; Intrathecal, NC; No contamination, and EU; Endotoxin unit.

Drug administration expressed the CD73, CD90, CD105, and CD44 markers
and almost lacked expressions of CD34, CD45 (Fig.2).
All patients took rilozule (100 mg) twice a day. If
needed, patients received medications for symptom
control or nursing support.

Clinical assessment
The assessments included the comprehensive physical
examination, taking history about any new symptoms,
ALS-FRS (32, 33), FVC, laboratory analysis (liver,
kidney, thyroid function, serology, virology, urine analysis
and culture). We performed them at 6, 4, 2, and one week
before cell therapy and also 2, 4, 6, and 12 months after
cell transplantation.

Magnetic resonance imaging

Brain and spinal cord MRIs were performed one week
before and 12 months after the cell transplantation. The Fig.2: Expressions of bone marrow derived mesenchymal stromal cell
(BM-MSC) surface markers.
system used for scanning was the 1.5 Tesla system, (GE
System version 2000). The images were taken in the
sagittal, axial, and coronal planes with T1, T2 and flair Adverse events
fast spin-echo sequence.
Of 14 patients, 1 patient from each group was lost to
Statistical analysis follow up after cell injection and we continued the study
with 12 patients, 5 in IV group and 7 in IT group. 1 patient
We carried out the statistical analysis with IBM SPSS had hypotension (85/60 mmHg) immediately after the IV
Statistics for Windows, Version 22.0 (IBM Corp., Armonk, injection of the cell suspension. After infusion of 1000
NY, USA). In the present study, continuous variables were ml 0.9% sodium chloride, the blood pressure increased
expressed as mean ± standard error (SE). Repeated-measures to 105/80 mmHg with stable vital signs. In addition, 2
ANOVA were used to assess the effects of treatment and time
patients had headaches and nausea after the IT injection
(months) and treatment-by-time interactions on ALS-FRS
of the cell suspension that lasted for 24 hours, which we
and FVC. All statistical tests were 2-sided and P<0.05 was
considered statistically significant. attributed to the lumbar puncture. After hydration and use
of nonsteroidal anti-inflammatory drugs (NSAIDS), their
Results symptoms resolved. In addition, there was no report of
any major adverse events or new abnormal findings in the
Flow cytometry brain and spinal MRI scans during 12 months after the
Flow cytometry analysis showed that BM-MSCs highly cell transplantation (Table 3).
Cell J, Vol 20, No 4, Jan-Mar (Winter) 2019 595
 Nabavi et al.

Table 3: Adverse effects after cell transplantation Follow up

Adverse effect Patient
(n)
Time of
occurrence
Outcome In the IV group, 5 patients completed the 12 month
(weeks) follow up and 1 patient was lost to follow up after the cell
transplantation. One patient, a 50-year old man with limb
Neurological adverse onset ALS, needed percutaneous endoscopic gastrostomy
events
(PEG) placement 8 months after the cell injection and due
Unconsciousness 0 0 to worsening the respiratory conditions. He underwent the
Dizziness 0 0 tracheostomy 10 months after the injection. This patient
died at the end of the study due to the respiratory infection.
Headache 2 1 Improved Other patients had decreased ALS-FRS and FVC levels
after
treatment during the 12 months of follow up which indicated disease
progression in compare with before cell injection (Fig.3).
Neck stiffness 0 0
Nausea and vomiting 2 1 Improved A
after
treatment

Hypotension 1 1 Improved
after
treatment

Motor dysfunction 0 0
Sensory dysfunction 0 0
Sphincter dysfunction 0 0
Seizures 0 0
Vertigo 0 0
Visual impairment 0 0
B

Allergic reactions
Fever 0 0
Apnea 0 0
Dyspnea 0 0
Anaphylaxis 0 0
Urticaria 0 0
Erythema 0 0
Flashing 0 0 Fig.3: The trend of amyotrophic lateral sclerosis-functional rating scale
(ALS-FRS) and forced vital capacity during 12 month follow up in patients
of both group. A. ALS-FRS and B. Forced vital capacity (FVC) in the
Local adverse events intravenous (IV) and intrathecal (IT) groups due to worsening of patients’
conditions. ALS-FRS and FVC data are mean ± SEM.
Phlebitis 0 0
Infection 0 0 In the IT group, 7 patients completed the 12 month follow
Hematoma 0 0 up and 1 patient was lost to follow up after the cell injection.
One patient, a 39-year old man with limb onset ALS needed
Other adverse events
PEG placement and a tracheostomy due to worsening of
his bulbar symptoms. We observed worsening of ALS and
Diarrhea 0 0 FVC percentages during 12 months of follow up in the
Constipation 0 0 other patients of this group (Fig.3). As presented in Figure
3, for ALS-FRS, repeated-measures ANOVA indicated a
Bronchitis 0 0 significant time effect (P<0.001) but no significant treatment
Pneumonia 0 0 effect (P=0.269). For FVC, the results of repeated-measures
ANOVA also showed a significant time effect (P<0.001) but
Pulmonary emboli 0 0
no significant treatment effect (P=0.731). Table S1 and Figure
Respiratory failure 0 0 S1 summarizes additional ALS-FRS and FVC information for
Arrhythmia 0 0 the study groups (See Supplementary Online Information at
www.celljournal.org).
Cell J, Vol 20, No 4, Jan-Mar (Winter) 2019 596
MSC for ALS

Discussion safe and feasible. To show the therapeutic effect of these

approaches, we should perform additional clinical trials
We designed the present study to confirm the safety and with more patients.
feasibility of IV and IT transplantations of BM-MSCs in
patients with ALS and compare the effects of each route Acknowledgements
of cell injection on prevention of disease progression.
At the end of follow-up period we observed no local or This study was supported by Royan Institute. The
systemic adverse effects or immediate reactions according authors have no commercial, proprietary or financial
to the clinical and laboratory assessments. One patient interests in the products or companies described in this
from the IV group experienced hypotension during the article.
cell suspension infusion and 2 patients from the IT group
complained of headaches and nausea following the IT Authors’ Contributions
injection. Symptoms resolved in all of these patients after N.A.; Designed the study, oversaw data acquisition and
treatment. MRI scans did not show any new abnormal analysis, and edited the manuscript. S.M.N.; Confirmed
findings such as mass formations in the brain or spinal the enrolment of screened patients, performed the
cord. These results confirmed the safety of either cell injections and clinical assessments during follow up. L.A.;
type or routes of administration. Numerous studies Performed patients’ screening for enrolment, followed the
have demonstrated the safety of BM-derived MSCs, patients after cell transplantation, monitored the clinical
which were similar to the current study (9, 15, 34, 35),
evaluation and data collection. N.J., T.B., F.A., S.M.,
but the disputable case was the transplantation pathway.
V.A.; Performed cell isolation, culture, and preparation
Different methods of tracing in animals have shown that
MSCs migrate after an IV injection and can be attracted to of the cell suspension. L.S.; Anesthetized and monitored
the damaged areas (36). The IT pathway is a direct route the patients during the injections. F.M.; Performed the
to reach the cerebrospinal fluid (CSF), thus the dynamic bone marrow aspiration. S.E.H.; Monitored the patients
flow of the CSF helps the cells to circulate simply through during and after the cell transplantation. All authors read
the brain and spinal cord, and access impaired areas (9, and approved the final manuscript.
20, 37, 38) . According to these mechanisms, we expected
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