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Safety and Feasibility of Repeated Intrathecal Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells in Patients with Neurological Diseases.

ABSTRACT: Mesenchymal stromal cells (MSCs) have become the most commonly used adult stem cells in regenerative medicine. Preclinical studies have shown that MSCs-based therapy is a potential new treatment approach for neurological diseases. Intrathecal injection has unique feature which allows stem cells to directly migrate to the lesion site in patients with central nervous system (CNS) diseases. In this study, we evaluate the safety and feasibility of intrathecal allogeneic bone marrow-derived MSCs (BM-MSCs) in patients with neurological diseases. This open-label clinical study included 37 patients (14 diseases). Eligible patients underwent a baseline assessment and were intrathecally injected with allogeneic BM-MSCs (1 × 10⁶?cells/kg, 4 consecutive treatments at 1-week intervals). After four infusions, the patients were followed up for at least 6 months. Adverse events, cerebrospinal fluid (CSF) test results, clinical symptoms, physical examination, and haematological and imaging examinations were used to assess the safety and feasibility of the treatment. Also, we performed a systematic review of the safety of all types of intrathecal stem cells and compared our result to previous studies. In our study, the highest adverse event was a slight ache at the injection site (4.11%), followed by fever (3.42%) and mild headache (2.05%). No severe adverse events were reported. After the intrathecal injections, the white blood cell (WBC) counts in the CSF increased in 30 patients and the protein concentration in the CSF exceeded the normal range in 26 patients, while other CSF indicators remained normal. Moreover, these patients had no suspected manifestations of CNS infection. Haematological and imaging examinations showed no abnormal changes after BM-MSCs infusion. Compared with previous studies, the incidence of adverse events was nearly consistent or even lower for headache, fever, nausea, and neck pain. In conclusion, repeated intrathecal allogeneic BM-MSCs are safe, feasible, and promising for the treatment of patients with neurological diseases.

SUBMITTER: Pan K

PROVIDER: S-EPMC6683773 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Safety and Feasibility of Repeated Intrathecal Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells in Patients with Neurological Diseases.

Pan Kuang K Deng Lingna L Chen Peiying P Peng Qingxia Q Pan Jingrui J Wu Yanfeng Y Wang Yidong Y

Stem cells international 20190725

Mesenchymal stromal cells (MSCs) have become the most commonly used adult stem cells in regenerative medicine. Preclinical studies have shown that MSCs-based therapy is a potential new treatment approach for neurological diseases. Intrathecal injection has unique feature which allows stem cells to directly migrate to the lesion site in patients with central nervous system (CNS) diseases. In this study, we evaluate the safety and feasibility of intrathecal allogeneic bone marrow-derived MSCs (BM- ...[more]

PMID: 31428161

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Project description:UnlabelledStem 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.SignificanceStem 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.

Project description:IntroductionMesenchymal stromal cells (MSCs) have opened a new window to treat inflammatory and non-inflammatory diseases. Nonetheless, their clinical applications require rigorous control and monitoring procedures to ensure full compliance with the principles of good manufacturing practice (GMP). Various evaluations should be passed in conjunction with the development of these newly emerging therapeutic products from bench-to-bedside. These evaluations include in vitro characterization, preclinical studies, and clinical trials to ensure product safety and efficacy. Therefore, a robust and well-designed preclinical study is critical to confirm product safety. This study aims to determine the probable toxicity effects of local and systemic injections of cryopreserved human bone marrow-derived clonal MSCs (BM-cMSCs) during subacute and subchronic periods of time.MethodsBM-cMSCs were characterized according to the International Society for Cell and Gene Therapy (ISCT) criteria for MSCs. Both safety and toxicity of the BM-cMSCs population produced under GMP-compatible conditions were assessed in both sexes of Sprague Dawley (SD) rats via systemic intravenous (IV) administration and local injection in intervertebral disc (IVD). Behavioral changes, clinical signs of toxicity, and changes in body weight, water and food consumption were the important variables for product toxicity testing over 14 consecutive days during the subacute period and 90 consecutive days during the subchronic period. At the end of the assessment periods, the rats were killed for histopathology analysis of the target tissues. The BM-cMSCs potential for tumorigenicity was checked in nude mice.ResultsSingle IV and IVD injections of BM-cMSCs did not cause significant signs of clinical toxicity, or changes in laboratory and histopathology data during the subacute (14 day) and subchronic (90 day) periods. Ex vivo-expanded and cryopreserved BM-cMSCs did not induce tumor formation in nude mice.ConclusionThe results suggest that local and systemic administrations of xenogeneic BM-cMSCs in both sexes of SD rats do not cause toxicity during the subacute and subchronic periods of time. Also, BM-cMSCs were non-tumorigenic in nude mice.

Dataset Information

Safety and Feasibility of Repeated Intrathecal Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells in Patients with Neurological Diseases.

Publications

Safety and Feasibility of Repeated Intrathecal Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells in Patients with Neurological Diseases.

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