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Cited by 129Amyotrophic Lateral Sclerosis ResearchSpinal Cord Injury ResearchPluripotent Stem Cells Research

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Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis: A Long-Term Outcome

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Mazzini, Letizia, Gelati, Maurizio, Profico, Daniela Celeste, Sorarù, Gianni, Ferrari, Daniela, Copetti, Massimiliano, Muzi, Gianmarco, Ricciolini, Claudia, Carletti, Sandro, Giorgi, Cesare, Spera, Cristina, Frondizi, Domenico, Masiero, Stefano, Stecco, Alessandro, Cisari, Carlo, Bersano, Enrica, De Marchi, Fabiola, Sarnelli, Maria Francesca, Querin, Giorgia, Cantello, Roberto, Petruzzelli, Francesco, Maglione, Annamaria, Zalfa, Cristina, Binda, Elena, Visioli, Alberto, Trombetta, Domenico, Torres, Barbara, Bernardini, Laura, Gaiani, Alessandra, Massara, Maurilio, Paolucci, Silvia, Boulis, Nicholas M., Vescovi, Angelo L., on behalf of the ALS-NSCs Trial Study Group·2019·Stem Cells Translational Medicine
DOI 10.1002/sctm.18-0154PMC PMC6708070
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Abstract

The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887–897

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Figures

Figure 1 Magnetic resonance imaging follow‐up in patient ISS‐799. Turbo Spine Echo T2‐weighted sequences acquired on sagittal plane before and 1, 3, 6, 12, 18, 24, and 30 months after cervical stem cell implant showing no consequences on spinal cord of cervical laminectomy.
Figure 1 Magnetic resonance imaging follow‐up in patient ISS‐799. Turbo Spine Echo T2‐weighted sequences acquired on sagittal plane before and 1, 3, 6, 12, 18, 24, and 30 months after cervical stem cell implant showing no consequences on spinal cord of cervical laminectomy.CC BY-NC-ND · PubMed Central
Figure 2 Spinal cord fibre Tracking (A): Whole cervical spinal cord fiber tracking reconstruction; the arrow indicates the laminectomy and implant site. (B) Magnetic resonance imaging (MRI) 15 days after stem cell graft. Directional color‐coded fractional anisotropy map at the implant site level, obtained from diffusion tensor imaging acquisition, with evidence of apparent diffusion coefficient map. (C–E): Follow‐up MRI with directional fractional anisotropy map and apparent diffusion coefficient map, respectively, at 12 months, 24 months, and 30 months.
Figure 2 Spinal cord fibre Tracking (A): Whole cervical spinal cord fiber tracking reconstruction; the arrow indicates the laminectomy and implant site. (B) Magnetic resonance imaging (MRI) 15 days after stem cell graft. Directional color‐coded fractional anisotropy map at the implant site level, obtained from diffusion tensor imaging acquisition, with evidence of apparent diffusion coefficient map. (C–E): Follow‐up MRI with directional fractional anisotropy map and apparent diffusion coefficient map, respectively, at 12 months, 24 months, and 30 months.CC BY-NC-ND · PubMed Central
Figure 3 Longitudinal progression of ALS‐FRS‐R score in the 3‐month period of natural history observation and 12 months after transplantation in the three groups of patients. Group A (upper left panel) group B (upper right panel), and group C (lower left panel). Mean values (lower right panel). Abbreviation: ALS‐FRS‐R, amyotrophic lateral sclerosis‐functional rating scale revised.
Figure 3 Longitudinal progression of ALS‐FRS‐R score in the 3‐month period of natural history observation and 12 months after transplantation in the three groups of patients. Group A (upper left panel) group B (upper right panel), and group C (lower left panel). Mean values (lower right panel). Abbreviation: ALS‐FRS‐R, amyotrophic lateral sclerosis‐functional rating scale revised.CC BY-NC-ND · PubMed Central
Figure 4 Longitudinal progression of FVC (%) score in the 3‐month period of natural history observation and 12 months after transplantation in the three groups of patients. Group A (upper left panel) group B (upper right panel), and group C (lower left panel). Mean values (lower right panel). Abbreviation: FVC, forced vital capacity.
Figure 4 Longitudinal progression of FVC (%) score in the 3‐month period of natural history observation and 12 months after transplantation in the three groups of patients. Group A (upper left panel) group B (upper right panel), and group C (lower left panel). Mean values (lower right panel). Abbreviation: FVC, forced vital capacity.CC BY-NC-ND · PubMed Central
Figure 5 Cytokines production evaluation (A): VEGF quantification in conditioned media during differentiation process modulated by saline or CSF derived from patients with amyotrophic lateral sclerosis (ALS) or healthy volunteers. (B): OPN quantification in conditioned media during differentiation process modulated by saline or cerebrospinal fluid derived from patients with ALS or healthy volunteers. Abbreviations: OPN, osteopontin; VEGF, vascular endothelial growth factor.
Figure 5 Cytokines production evaluation (A): VEGF quantification in conditioned media during differentiation process modulated by saline or CSF derived from patients with amyotrophic lateral sclerosis (ALS) or healthy volunteers. (B): OPN quantification in conditioned media during differentiation process modulated by saline or cerebrospinal fluid derived from patients with ALS or healthy volunteers. Abbreviations: OPN, osteopontin; VEGF, vascular endothelial growth factor.CC BY-NC-ND · PubMed Central

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Research works printed but not linked: 3

  1. Brooks, 2000, Amyotroph Lateral Scler Other Motor Neuron Disorder, 293
  2. McNair, 1992, Revised Manual for the Profile of Mood States
  3. O'Boyle, 1993, The Schedule for the Evaluation of Individual Quality of Life (SEIQoL): A Direct Weighting Procedure for Quality of Life Domains (SEIQoL-DW)

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Metadata

Authors
Mazzini, L., Gelati, M., Profico, D. C., Sorarù, G., Ferrari, D., Copetti, M., Muzi, G., Ricciolini, C., Carletti, S., Giorgi, C., Spera, C., Frondizi, D., Masiero, S., Stecco, A., Cisari, C., Bersano, E., De Marchi, F., Sarnelli, M. F., Querin, G., Cantello, R., Petruzzelli, F., Maglione, A., Zalfa, C., Binda, E., Visioli, A., Trombetta, D., Torres, B., Bernardini, L., Gaiani, A., Massara, M., Paolucci, S., Boulis, N. M., Vescovi, A. L., & on behalf of the ALS-NSCs Trial Study Group
Affiliations
  • Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
  • Casa Sollievo della Sofferenza (IT)
  • d Department of Neuroscience University of Padua, Padua, Italy
  • University of Milano-Bicocca (IT)
  • Azienda Ospedaliera S.Maria (IT)
  • University of Padua (IT)
  • Azienda Ospedaliero Universitaria Maggiore della Carita (IT)
  • a Eastern Piedmont University, “Maggiore della Carità” Hospital Dipartimento di Neurologia, Novara
  • l StemGen SpA, Milan, Italy
  • n Fondazione IRCCS Casa Sollievo della Sofferenza Cytogenetics Unit, San Giovanni Rotondo, Foggia, Italy
  • Emory University (US)
Corresponding author
  • Mazzini, Letizia
  • Vescovi, Angelo L.
ORCID
Venue
Stem Cells Translational Medicine
Publisher
Oxford University Press (OUP)
Published
2019-05-18
Volume
8
Issue
9
Pages
887-897
ISSN
  • 2157-6564 (ISSN-L)
  • 2157-6580
DOI
10.1002/sctm.18-0154
PMC
PMC6708070
OpenAlex
W2945776234
Cited by
128
References
42
Citations by year
2026: 10 · 2025: 21 · 2024: 19 · 2023: 23 · 2022: 14 · 2021: 20 · 2020: 17 · 2019: 3
FWCI
9.13
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cells Translational Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
amyotrophic lateral sclerosis, neural stem cells, cell therapy safety, disease progression, ALSFRS-R, long-term outcomes, ex vivo cell expansion
MeSH terms
Adult, Aged, Amyotrophic Lateral Sclerosis, Brain, Female, Glial Fibrillary Acidic Protein, Humans, Injections, Spinal, Magnetic Resonance Imaging, Male, Middle Aged, Pain, Pilot Projects, Spinal Cord, Treatment Outcome, Brain-Derived Neurotrophic Factor, Stem Cell Transplantation, Vascular Endothelial Growth Factor A, Young Adult, Neural Stem Cells

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