Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study

Abstract

Background aims

Mesenchymal stem cells/marrow stromal cells (MSC) represent a promising tool for stem cell-based clinical trials in amyotrophic lateral sclerosis (ALS). We present the results of long-term monitoring of 19 ALS patients enrolled in two phase I clinical trials of autologous MSC transplantation

Methods

Nineteen patients (11 male and eightfemale) with ALS were enrolled in two consecutive phase I clinical trials. The patients were followed-up for 6–9 months and then treated with autologous MSC isolated from bone marrow and implanted into the dorsal spinal cord with a surgical procedure. The patients were monitored regularly before and after transplantation with clinical, psychological and neuroradiologic assessments every 3 months, at the tertiary referral ALS center in Novara (Italy), until death

Results

Follow-up brain magnetic resonance imaging (MRI) revealed no structural changes (including tumor formation) relative to the baseline throughout the follow-up. There was no deterioration in the psychosocial status and all patients coped well. No clear clinical benefits were detected in these patients but the recruitment and selection of appropriate patients into larger trials will be needed to test the efficacy of the treatment

Conclusions

This study is the first to show the safety of MSC transplantation in the central nervous system during a follow-up of nearly 9 years, and is in support of applying MSC-based cellular clinical trials to neurodegenerative disorders.

Introduction

Stemcell-based therapies represent a new possible strategy for amyotrophic lateral sclerosis (ALS) clinical research aimed at cell replacement and neuroprotection. Experimental evidence in pre-clinical models of neurologic diseases suggests that mesenchymal stromal cells (MSC) provide a promising approach to achieving neural repair and protection (1). Many findings of several studies have indicated a range of effects of MSC in the central nervous system (CNS) that might be beneficial in ALS. MSCpossess immunomodulating properties exerted in vitro on cell populations of both adpative and innate immunity (2). Many effects produced by the MSC are explained by paracrine mechanisms, including a potent anti-inflammatory capacity, the direct release of anti-apoptotic and neurotrophic factors, the ability to induce other cells, such as microglia, to acquire a protective phenotype, and the ability to induce proliferation of local neural progenitor cells (1,2). In vivo transplantation of human (h)MSC into the lumbar spinal cord of asymptomatic SOD1-G93A (3) mice results in the delay of both anatomical and functional signs and symptoms. hMSCsurvive forlong periods following transplantation close to the cell bodies of motor neurons (MN), even though they very rarely express neural markers such as GFAP and MAP2. hMSCdelay the onset of astrogliosis and microglial activation, MN cell death, and the impairment of motor behavior (4).

Preliminary data have revealed that intraspinal autologous MSC transplantation is feasible and safe during short- and medium-term follow-up (5., 6., 7.). To date only a few studies have reported the results of clinical trials (5., 6., 7., 8., 9., 10., 11., 12., 13., 14.) with stem cells, and mostly refer to short-term follow-ups. All the studies are small phase I clinical trials. Although the type and number of cells and delivery routes are different, all these trials show a satisfactory safety and tolerability of the experimental protocols. We present the results of the long-term monitoring of 19 ALS patients enrolled in two phase I clinical trials of autologous MSC transplantation.