Human neural stem cell transplantation in ALS: Initial results from a phase I trial

Letizia Mazzini, Maurizio Gelati, Daniela Celeste Profico, Giada Sgaravizzi, Massimo Projetti Pensi, Gianmarco Muzi, Claudia Ricciolini, Laura Rota Nodari, Sandro Carletti, Cesare Giorgi, Cristina Spera, Frondizi Domenico, Enrica Bersano, Francesco Petruzzelli, Carlo Cisari, Annamaria Maglione, Maria Francesca Sarnelli, Alessandro Stecco, Giorgia Querin, Stefano MasieroRoberto Cantello, Daniela Ferrari, Cristina Zalfa, Elena Binda, Alberto Visioli, Domenico Trombetta, Antonio Novelli, Barbara Torres, Laura Bernardini, Alessandro Carriero, Paolo Prandi, Serena Servo, Annalisa Cerino, Valentina Cima, Alessandra Gaiani, Nicola Nasuelli, Maurilio Massara, Jonathan Glass, Gianni Sorarù, Nicholas M. Boulis, Angelo L. Vescovi

Research output: Contribution to journalArticle

Abstract

Background: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Methods: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. Results: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. Conclusions: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.

Original languageEnglish
Article number17
JournalJournal of Translational Medicine
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 27 2015

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Neural Stem Cells
Stem Cell Transplantation
Stem cells
Surgery
Polyethylene glycols
Ventilation
Brain
Tissue
Microinjections
Neurosurgical Procedures
Safety
Ethics Committees
Clinical Trials, Phase I
Spontaneous Abortion
Cell- and Tissue-Based Therapy
Respiratory Insufficiency
Walking
Disease Progression
Autopsy
Spinal Cord

Keywords

  • Advanced therapies
  • ALS
  • Cell therapy
  • Foetal human neural stem cells
  • Phase I trial

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Human neural stem cell transplantation in ALS : Initial results from a phase I trial. / Mazzini, Letizia; Gelati, Maurizio; Profico, Daniela Celeste; Sgaravizzi, Giada; Projetti Pensi, Massimo; Muzi, Gianmarco; Ricciolini, Claudia; Rota Nodari, Laura; Carletti, Sandro; Giorgi, Cesare; Spera, Cristina; Domenico, Frondizi; Bersano, Enrica; Petruzzelli, Francesco; Cisari, Carlo; Maglione, Annamaria; Sarnelli, Maria Francesca; Stecco, Alessandro; Querin, Giorgia; Masiero, Stefano; Cantello, Roberto; Ferrari, Daniela; Zalfa, Cristina; Binda, Elena; Visioli, Alberto; Trombetta, Domenico; Novelli, Antonio; Torres, Barbara; Bernardini, Laura; Carriero, Alessandro; Prandi, Paolo; Servo, Serena; Cerino, Annalisa; Cima, Valentina; Gaiani, Alessandra; Nasuelli, Nicola; Massara, Maurilio; Glass, Jonathan; Sorarù, Gianni; Boulis, Nicholas M.; Vescovi, Angelo L.

In: Journal of Translational Medicine, Vol. 13, No. 1, 17, 27.01.2015.

Research output: Contribution to journalArticle

Mazzini, L, Gelati, M, Profico, DC, Sgaravizzi, G, Projetti Pensi, M, Muzi, G, Ricciolini, C, Rota Nodari, L, Carletti, S, Giorgi, C, Spera, C, Domenico, F, Bersano, E, Petruzzelli, F, Cisari, C, Maglione, A, Sarnelli, MF, Stecco, A, Querin, G, Masiero, S, Cantello, R, Ferrari, D, Zalfa, C, Binda, E, Visioli, A, Trombetta, D, Novelli, A, Torres, B, Bernardini, L, Carriero, A, Prandi, P, Servo, S, Cerino, A, Cima, V, Gaiani, A, Nasuelli, N, Massara, M, Glass, J, Sorarù, G, Boulis, NM & Vescovi, AL 2015, 'Human neural stem cell transplantation in ALS: Initial results from a phase I trial', Journal of Translational Medicine, vol. 13, no. 1, 17. https://doi.org/10.1186/s12967-014-0371-2
Mazzini, Letizia ; Gelati, Maurizio ; Profico, Daniela Celeste ; Sgaravizzi, Giada ; Projetti Pensi, Massimo ; Muzi, Gianmarco ; Ricciolini, Claudia ; Rota Nodari, Laura ; Carletti, Sandro ; Giorgi, Cesare ; Spera, Cristina ; Domenico, Frondizi ; Bersano, Enrica ; Petruzzelli, Francesco ; Cisari, Carlo ; Maglione, Annamaria ; Sarnelli, Maria Francesca ; Stecco, Alessandro ; Querin, Giorgia ; Masiero, Stefano ; Cantello, Roberto ; Ferrari, Daniela ; Zalfa, Cristina ; Binda, Elena ; Visioli, Alberto ; Trombetta, Domenico ; Novelli, Antonio ; Torres, Barbara ; Bernardini, Laura ; Carriero, Alessandro ; Prandi, Paolo ; Servo, Serena ; Cerino, Annalisa ; Cima, Valentina ; Gaiani, Alessandra ; Nasuelli, Nicola ; Massara, Maurilio ; Glass, Jonathan ; Sorarù, Gianni ; Boulis, Nicholas M. ; Vescovi, Angelo L. / Human neural stem cell transplantation in ALS : Initial results from a phase I trial. In: Journal of Translational Medicine. 2015 ; Vol. 13, No. 1.
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abstract = "Background: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanit{\`a} and the competent Ethics Committees and was monitored by an external Safety Board. Methods: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. Results: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. Conclusions: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.",
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T1 - Human neural stem cell transplantation in ALS

T2 - Initial results from a phase I trial

AU - Mazzini, Letizia

AU - Gelati, Maurizio

AU - Profico, Daniela Celeste

AU - Sgaravizzi, Giada

AU - Projetti Pensi, Massimo

AU - Muzi, Gianmarco

AU - Ricciolini, Claudia

AU - Rota Nodari, Laura

AU - Carletti, Sandro

AU - Giorgi, Cesare

AU - Spera, Cristina

AU - Domenico, Frondizi

AU - Bersano, Enrica

AU - Petruzzelli, Francesco

AU - Cisari, Carlo

AU - Maglione, Annamaria

AU - Sarnelli, Maria Francesca

AU - Stecco, Alessandro

AU - Querin, Giorgia

AU - Masiero, Stefano

AU - Cantello, Roberto

AU - Ferrari, Daniela

AU - Zalfa, Cristina

AU - Binda, Elena

AU - Visioli, Alberto

AU - Trombetta, Domenico

AU - Novelli, Antonio

AU - Torres, Barbara

AU - Bernardini, Laura

AU - Carriero, Alessandro

AU - Prandi, Paolo

AU - Servo, Serena

AU - Cerino, Annalisa

AU - Cima, Valentina

AU - Gaiani, Alessandra

AU - Nasuelli, Nicola

AU - Massara, Maurilio

AU - Glass, Jonathan

AU - Sorarù, Gianni

AU - Boulis, Nicholas M.

AU - Vescovi, Angelo L.

PY - 2015/1/27

Y1 - 2015/1/27

N2 - Background: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Methods: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. Results: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. Conclusions: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.

AB - Background: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Methods: Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. Results: No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. Conclusions: We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material.

KW - Advanced therapies

KW - ALS

KW - Cell therapy

KW - Foetal human neural stem cells

KW - Phase I trial

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