Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis

Abstract

Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). The aim of this open-label phase I clinical trial was to evaluate the safety of two repeated intrathecal injections of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in ALS patients. Eight patients with definite or probable ALS were enrolled. After a 3-month lead-in period, autologous MSCs were isolated two times from the BM at an interval of 26 days and were then expanded in vitro for 28 days and suspended in autologous cerebrospinal fluid. Of the 8 patients, 7 received 2 intrathecal injections of autologous MSCs (1 × 10(6) cells per kg) 26 days apart. Clinical or laboratory measurements were recorded to evaluate the safety 12 months after the first MSC injection. The ALS Functional Rating Scale-Revised (ALSFRS-R), the Appel ALS score, and forced vital capacity were used to evaluate the patients' disease status. One patient died before treatment and was withdrawn from the study. With the exception of that patient, no serious adverse events were observed during the 12-month follow-up period. Most of the adverse events were self-limited or subsided after supportive treatment within 4 days. Decline in the ALSFRS-R score was not accelerated during the 6-month follow-up period. Two repeated intrathecal injections of autologous MSCs were safe and feasible throughout the duration of the 12-month follow-up period.

Significance: Stem cell therapy is an emerging alternative therapeutic or disease-modifying strategy for amyotrophic lateral sclerosis (ALS). To the authors' best knowledge, there are no clinical trials to evaluate the safety of repeated intrathecal injections of autologous bone marrow mesenchymal stromal cells in ALS. After the clinical trial (phase I/II) was conducted, the stem cell (HYNR-CS, NEURONATA-R) was included in the revision of the regulations on orphan drug designation (number 160; December 31, 2013) and approved as a New Drug Application (Department of Cell and Gene Therapy 233; July 30, 2014) by the Korean Food and Drug Administration. The phase II trial is expected to be reported later.

Keywords: Amyotrophic lateral sclerosis; Clinical trials; Intrathecal; Mesenchymal stromal cells.

Figure 1.

Study design of the trial. This study consists of a 3-month lead-in period, a 4-month initial follow-up period, and an 8-month secondary follow-up period. The first MSC injection was performed at V5 (+0 months). The BM extraction at V3 (−1 months) was for the first injection at V5. The BM extraction at V4 (2 days prior to V5) was for cells for the first injection at V6. Abbreviations: BME, bone marrow extraction; MSC, mesenchymal stromal cell; Mo, months; V, visit.

Figure 2.

Progression of the ALSFRS-R score, the AALS score, and the FVC. Patient S-001 died prior to the bone marrow extraction. When calculating the mean and standard deviation, the data from patient S-001 were not included. Abbreviations: AALS, Appel ALS score; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised; FVC, forced vital capacity; Mo, months.