8. Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in chronic spinal cord injury patients: 7 case series

Abstract

BACKGROUND CONTEXT

In the chronic phase, functional recovery of spinal cord injury (SCI) without any therapeutic intervention is highly limited. Therefore, new treatments are desired to enhance residual function, with the important objection of increasing the quality of life in chronic SCI patients. Intravenous infusion of auto serum-expanded autologous bone marrow-derived mesenchymal stem cells (MSCs) for acute SCI patients has shown the safety and potential therapeutic efficacy of this approach. However, the clinical use for the chronic phase of SCI has not been studied.

PURPOSE

This study explores safety, feasibility and potential improvement in functional status after intravenous infusion of MSCs in chronic severe SCI patients.

STUDY DESIGN/SETTING

We report a case series of 7 chronic SCI patients with AIS grades C and D who received autoserum-expanded autologous MSCs. Statistical analyses were performed using JMP 11.1 for Windows (SAS Institute Inc.). The differences between status prior to MSC infusion and 6 months postinfusion, for both ISCSCI-92 and SCIM-III among the groups were analyzed using one-way analysis of variance followed by Bonferroni's post hoc tests. Data are expressed as mean ± standard error of the mean. Differences were considered statistically significant at p < 0.05.

PATIENT SAMPLE

The patients included 5 men and 2 women who ranged 20 to 52 years old (mean 39.6 years old). After careful examination, 7 patients with chronic SCI were included in this study based on the following inclusion and exclusion criteria. Inclusion criteria: (1) 180 days or more after onset of SCI, (2) age at least 18 years old, (3) rehabilitation can be performed more than 4 units per day, (4) the written informed consent obtained as much as possible from subjects (if the subject does not have ability to write, the written informed consent obtained from legal representative alone).

OUTCOME MEASURES

Each participant's status on SCI scales including American Spinal Injury Association (ASIA) impairment scale, International Standards for Neurological Classification of Spinal Cord Injury (ISCSCI-92), and Spinal Cord Independence Measure-III (SCIM-III) was assessed from 0 to 14 days prior to MSC infusion, and at 90 (± 14) and 180 (± 14) days post-MSC infusion, by at least 2 board-certified orthopedic surgeons who were not blinded. The primary outcome measure of this clinical study was the proportion of cases whose ASIA scale improved one point or more at 180 ± 14 days post-MSC infusion compared to the functional status just prior to MSC infusion (0-14 days). All patients were monitored closely during and within 24 h of the autologous human MSC injections. Oxygen saturation, body temperature, electrocardiogram, blood pressure, pulse and respiratory rate were carefully monitored before and after injection. Chest films were obtained for each subject before and after autologous MSC infusion. At 6 months post MSC infusion, all participants underwent radiological examinations and routine blood/urine examinations to confirm the absence of any adverse effects.

METHODS

We provided an extensive rehabilitation protocol to all participants prior to MSC infusion in order to exclude the potential effects of rehabilitation alone and evaluate MSC-specific effects. Briefly, all participant patients with chronic SCI received formal rehabilitation (at least 80 min/weekday for 4 weeks) and continue formal rehabilitation until they showed no further improvements in ISCSCI-92 scores (more than 2 points) for the last 2 weeks prior to MSC infusion. Thus, we expected to evaluate the therapeutic effects of MSC infusion in addition to the effects of rehabilitation therapy. If the patients required more than 2 weeks to reach an ISCSCI-92 score plateau, we continued formal rehabilitation until they showed no further improvement for the next 2 weeks.

For cell preparation, autologous human MSCs were prepared using previously described methods.

RESULTS

Seven patients ranging from 20 to 52 (average: 39.6 ± 5.0, median: 48) years and of both genders were studied. The autologous MSCs were intravenously infused between 1.3 to 18 years post-SCI. No serious adverse events were associated with cell injection. Anemia after peripheral blood collection (6 cases) and local pain at the bone marrow aspiration site immediately after bone marrow collection (1 case) were recorded as protocol-related adverse events (AE). However, all protocol-related AEs occurred before MSC infusion. Thus, there were no MSC-related AEs in this study. The time point of last assessment post-MSC infusion in this study was approximately 180 days after MSC infusion. One of 2 patients classified as AIS C prior to MSC improved to AIS D at 6 months post-MSC infusion. All AIS D participants (n=5) did not change the AIS grade 6 months after MSC infusion. The patients displayed gradual increases in motor scores with statistical significance at 90 and 180 days post-MSC infusion compared to before MSC infusions. Furthermore, the motor score at 180 days post-MSC infusion was higher than at 90 days post-MSC infusion as well. Sensory scores are shown before MSC infusion, at 90 and 180 days post-MSC infusion. The patients also exhibited gradual increases in SCIM scores with statistical significance at 90 and 180 days post-MSC infusion compared to before MSC infusions. The individual changes are shown in ISCSCI-92 scores, including motor and sensory scores and SCIM-III scores, in ASIA C and ASIA D patients before MSC infusion and 180 days post-MSC infusion. Motor and sensory functions at 6 months (± 14 days) showed higher points compared to scores prior to MSC infusion in all patients. In ASIA D, Motor and sensory scores at 6 months (± 14 days) showed higher points compared to scores prior to MSC infusion in all patients except one patient. In SCIM-III, the total scores at 6 months (± 14 days) are higher compared to the scores prior to MSC infusion in all patients in all groups.

CONCLUSIONS

We report the detailed clinical record of infused autologous, auto-serum expanded MSCs in 7 chronic SCI patients. Our observations support safety, feasibility, and provide initial data that suggests potential functional improvements following MSC infusion. This case series underscores the importance of a future large-scale controlled clinical study in chronic SCI patients to determine efficacy.

FDA Device/Drug Status

This abstract does not discuss or include any applicable devices or drugs.