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Short Communication | DOI: https://doi.org/
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Received: 30 November -0001 | Accepted: 20 September 2018 | Published: 24 September 2018
Keywords: Spinal cord injury, Cell therapy, Mesenchymal stromal cells
Background. Recent clinical studies suggest that cell therapy with autologous mesenchymal stromal cells (MSCs) improves to patients with spinal cord injury (SCI). Objective. The current study aimed to know the long-term evolution of the improvement in sensitivity and motor scores in patients with chronic and incomplete SCI who were treated with repeated intrathecal administrations of autologous mesenchymal stromal cells (MSCs) supported in autologous plasma.
Methods. The 8 patients studied received a total of 120 x 106 MSCs in four doses of 30 x 106 MSCs each, and were followed by according to American Spinal Injury Association (ASIA) assessment during 3 years.
Results. The patients showed an early improvement, mainly in the course of the first six months. After 18 months of follow-up no new improvement was observed. At this time point, the results obtained with respect to baseline scores were maintained, at least until the end of the follow-up.
Conclusion. Although these data can not be extrapolated to other protocols of cell therapy in patients with SCI, the observation that the benefits obtained are maintained in the long-term is an important argument that supports the use of cell therapy with autologous MSCs for patients with SCI.
We studied by ASIA total scores, the long-term outcome in 8 patients with incomplete SCI that were previously included in a Clinical Trial approved by the Medical Research Committee of the Puerta de Hierro-Majadahonda Hospital and the Spanish Agency of Medicament and Health Products (AEMPS). In this Clinical Trial (ClinicalTrials.gov: NCT02165904) 10 patients were included, with a follow-up of 12 months, and signs of clinical improvement, mainly in sensitivity, were found 7. The objective of the current brief communication is to describe the long-term outcome in the motor and sensitivy improvement that was obtained after this type of cell therapy, but a follow-up of 36 months was possible only in 8 patients.
We used a cell therapy medicament (NC1) currently approved as a medicament under clinical investigation (PEI No. 12-141). This medicament consists of autologous MSCs and autologous plasma as its excipient. Data about NC1, including genetic studies, culture, formulation, packaging and phenotypic characterization of the MSCs are previously described 7, 8.
Treatment consisted of subarachnoid injection, by lumbar puncture, of 30 x 106 autologous MSCs obtained from bone marrow and supported in autologous plasma (month 1 of the study). It was repeated at month 4, 7 and 10, reaching a total administration of 120 x 106 MSCs for each patient. The patients were followed monthly, from the first administration of MSCs through month 12, and every six months from month 12 to the month 36 of follow-up. Assessment of total ASIA scores was used for the present study of long-term outcome, and clinical explorations were made simultaneously by two unique rehabilitators with experience in the application of the ASIA scale 9.
To study the differences between the scores of the ASIA total, of each six months with basal values, and the differences between different time points, the nonparametric Wilcoxon Rank test was used. All inferential procedures used α = 0.05 as the level of risk.
The ratio Male/Female (M/F) was 7/1. Two patients had a grade B in the ASIA study, 5 patients had a grade C, and one patient had a grade D at the start of cell therapy. SCI level was C5-C6 in three cases, L1 in three cases, D2 in one case, and D7-D8 in one case. The time elapsed since SCI until the beginnning of cell therapy ranged between 2.43 and 34.59 years (mean ± standard deviation = 14.65 ± 10.11 years).
Figure 1 shows the mean and standard deviation (SD) of ASIA total scores in the patients. They improved in sensitivity and motor scores immediately after the first administration of MSCs. Improvement was mainly in sensitivity scores. ASIA total scores mainly improved in the course of the first 6 months after cell therapy, but significant additional improvement was also observed between 6 and 12 months of follow-up (p = 0.0078). After 12 month of follow-up, significant increase of ASIA total score was not found (p = 0.25). Novertheless, two patients showed small additional improvement in sensitivity between 12 and 18 months. No improvements was observed from 18 months, and the ASIA total score obtained at this time point was maintained in all the patients, at 36 months of follow-up (Figure 2).
At 6 months follow-up
At 12 months follow-up
At 18 months follow up
At 24 months follow-up
At 30 months follow-up
At 36 months follow-up
In recent years growing evidence suggests the safety and benefit of cell therapy for patients with SCI 1-8. However, in cell therapy there are multiple factors that can influence the results, such as the variable morphology of SCI, the type and number of donor cells, their viability and potency, their route of administration and the different protocols that can be used 7, 10.
Recently, we reported that patients with chronic and incomplete SCI improved in sensitivity and motor function after repeated intrathecal administrations of autologous MSCs supported in autologous plasma7. ASIA assessment was used for clinical evaluation of the patients and they were followed for 12 months7. The present study responds to the need to know if the benefit obtained is maintained, increases or decreases in the long-term.
Our present findings confirm the benefit of intrathecal administrations of repeated doses of MSCs, achieving early improvement in the ASIA scores, mainly in the first months after the start of cell therapy. At least in the ASIA assessment, the prolongation of the follow-up suggests that after 18 months no greater improvement in sensitivity and motor scores should be expected. After three years of follow-up the improvements obtained remained in our patients.
At present, we do not know if these findings can be applied to patients with complete SCI, or if they can be different in patients treated with a greater number of MSCs, using a greater number of doses, or to patients treated through intralesional administrations, but the observation that the benefits obtained are maintained in the long-term is an important finding, supporting the use of cell therapy with autologous MSCs in patients with SCI.
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