Safety of repeated transplantations of neurotrophic factors‐secreting human mesenchymal stromal stem cells

Abstract

Background Therapies based on mesenchymal stem cells (MSC) have been shown to have potential benefit in several clinical studies. We have shown that, using a medium‐based approach, MSC can be induced to secrete elevated levels of neurotropic factors, which have been shown to have protective effects in animal models of neurodegenerative diseases. These cells, designated MSC‐NTF cells (Neurotrophic factor‐secreting MSC, also known as NurOwn™) derived from the patient's own bone marrow, have been recently used for Phase I/II and Phase IIa clinical studies in patients with Amyotrophic Lateral Sclerosis (ALS). In these studies, ALS patients were subjected to a single administration of autologous MSC‐NTF cells. The data from these studies indicate that the single administration of MSC‐NTF cells is safe and well tolerated. In a recently published case report, it was shown that repeated MSC‐NTF injections in an ALS patient treated on a compassionate basis were safe and well tolerated [Muscle Nerve 49:455‐457, 2014]. Methods In the current study we studied the toxicity and tolerability of three consecutive intramuscular injections (IM) of cryopreserved human MSC‐NTF cells in C57BL/B6 mice to investigate the effect of repeated administration of these cells. Results Monitoring of clinical signs and immune reactions showed that repeated injections of the cells did not lead to any serious adverse events. Pathology, histology and blood biochemistry parameters tested were found to be within normal ranges with no sign of tumor formation. Conclusions Based on these results we conclude that repeated injections of human MSC‐NTF are well tolerated in mice. The results of this study suggest that if the outcomes of additional clinical studies point to the need for repeated treatments, such option can be considered safe.

A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1G93A Rats

“…Although the majority of studies report on intraspinal or intrathecal injections, some studies showed interest in intramuscular injections, since the retraction of dying MN hampers the NMJ . In our study, the combined application into the SC, together with intramuscular injection, showed the best effect in several parameters.…”

Mesenchymal Stromal Cell Therapies for Neurodegenerative Diseases

“…First, MSCs have been reported to secrete neurotrophic growth factors, including glial cellederived neurotrophic factor (GDNF), vascular endothelial growth factor, and brain-derived neurotrophic factor (BDNF), 8,9 which can be further enhanced under specific culture conditions. 10 Neurotrophic growth factors have been found to improve neuronal survival in a number of preclinical models of neuron injury, including ALS, PD, and MSA transgenic animals [11][12][13][14][15][16][17] and nerve injury models. 12,18,19 Second, MSCs strongly modulate the immune system and can aid wound healing, and this mechanism has been exploited in disorders such as graftvs-host disease 20 and Crohn disease.…”

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

“…Stem cell therapy has been previously used on ASD children with long-term beneficial effects 57 . Bone marrow MSC transplantation has been proven to be safe to use in several clinical trials [58][59][60] . Mechanistically, bone marrow MSC transplantation was found efficient in promoting tissue regeneration, immunomodulation, and inflammatory reduction [61][62][63] .…”