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

• Type of Material: Article
• Authors: Letizia Mazzini, Eastern Piedmont University; Maurizio Gelati, Terni Hospital; Daniela Celeste Profico, Terni Hospital; Giada Sgaravizzi, Terni Hospital; Massimo Projetti Pensi, Terni Hospital; Gianmarco Muzi, Terni Hospital; Claudia Ricciolini, Terni Hospital; Laura Rola Nodari, IRCCS Casa Sollievo della Sofferenza; Sandro Carletti, “Santa Maria” Hospital; Cesare Giorgi, “Santa Maria” Hospital; Cristina Spera, “Santa Maria” Hospital; Frondizi Domenico, “Santa Maria” Hospital; Enrica Bersano, Eastern Piedmont University; Francesco Petruzzelli, IRCCS Casa Sollievo della Sofferenza; Carlo Cisari, Maggiore della Carità Hospital; Annamaria Maglione, IRCCS Casa Sollievo della Sofferenza; Maia Francesca Sarnelli, Eastern Piedmont University; Alessandro Stecco, Eastern Piedmont University; Giorgia Querin, University of Padua; Stefano Masiero, University of Padua; Roberto Cantello, Eastern Piedmont University; Daniela Ferrari, Bicocca University; Cristina Zalfa, Bicocca University; Elena Binda, Bicocca University; Alberto Visioli, Bicocca University; Domenico Trombetta, IRCCS Casa Sollievo della Sofferenza; Antonio Novelli, IRCCS Casa Sollievo della Sofferenza; Barbara Torres, IRCCS Casa Sollievo della Sofferenza; Laura Bernardini, IRCCS Casa Sollievo della Sofferenza; Alessandro Carriero, Eastern Piedmont University; Paolo Prandi, Eastern Piedmont University; Serena Servo, Eastern Piedmont University; Annalisa Cerino, Eastern Piedmont University; Valentina Cima, University of Padua; Alessandra Gaiani, University of Padua; Nicola Nasuelli, Eastern Piedmont University; Maurilio Massara, Maggiore della Carità Hospital; Jonathan Glass, Emory University; Gianni Soraru, University of Padua; Angelo L. Vescovi, Terni Hospital; Nicholas Boulis, Emory University
• Language: English
• Date: 2015-01-27
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Mazzini et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12967-014-0371-2
• Title of Journal or Parent Work: Journal of Translational Medicine
• ISSN: 1479-5876
• Volume: 13
• Issue: 1
• Start Page: 17
• End Page: 17
• Grant/Funding Information: The Fondazione Stefano Borgonovo also supported our research.; This trial was supported by the Revert Onlus Association and the Fondazione Cellule Staminali di Terni.; Special thanks go to the "ASSICURAZIONI GENERALI" group, whose continued sponsorship was fundamental to the success of this research.
• Keywords: PLATFORM; Science & Technology; Advanced therapies; NEUROSPHERES; Research & Experimental Medicine; ALS; INJECTION; Foetal human neural stem cells; Life Sciences & Biomedicine; BRAIN; Cell therapy; SAFETY OUTCOMES; AMYOTROPHIC-LATERAL-SCLEROSIS; VALIDATION; Phase I trial; CORD THERAPEUTICS DELIVERY; PRECURSORS; Medicine, Research & Experimental; MICROINJECTION
• Research Categories: Biology, Neuroscience; Health Sciences, Medicine and Surgery

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.