Mesenchymal stromal cells (MSC) are multipotent cells capable of differentiating into cells associated with multiple lineages [ 1 ]. MSC are being evaluated like a potential therapy for a wide variety of degenerative and immunological problems [ 2 ].
We have developed a culture-medium based method for inducing MSCs to secrete enhanced levels of multiple neurotrophic factors (NTFs) including glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic aspect (BDNF) vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) [ 3 ]. MSC-NTF cells (NurOwn® ) have been successfully used in clinical trials for amyotrophic lateral sclerosis (ALS) patients [ 4 ].
NTFs are small, normally occurring polypeptides that support the development and success of neurons [ 5 ]. NTFs are potent success factors for embryonic, neonatal, and adult neurons, and also have been evaluated in various neurodegenerative disease clinical trials in the last 25 years [ 6 , 7 ]. MSC-NTF cells that have been induced in order to enhanced secretion of NTFs, offer a novel method for at the same time delivering multiple NTFs to patients with neurodegenerative illnesses such as ALS, while leveraging the potential immunomodulatory therapeutic advantages of MSCs [ 8 ]. Furthermore, a recent study demonstrated possible therapeutic benefits of MSC-NTF cells in an animal model of autism [ 9 ].
ALS (also known as Lou Gehrig’ s disease) is really a rare, relentlessly progressive and lethal neurodegenerative disease. On the cellular level, ALS is characterized by the progressive deterioration of upper and lower motor neurons in the motor cortex, brainstem, and spinal cord leading to progressive functional impairment and eventually death [ 10 ].
Three clinical studies with NurOwn® (the MSC-NTF cell therapy) in ALS patients have been completed. The very first two open-label studies [ 4 ], confirmed that the therapy was safe and well tolerated either by the intrathecal (IT) or by the intramuscular (IM) route of management as well as by combined IT and IM administration. These types of studies demonstrated preliminary indications of efficacy, by decreasing the rate of disease progression, as measured by the WIE Functional Rating Scale-Revised (ALSFRS-R) score. The recently finished US phase 2 multicenter double-blind placebo-controlled study verified these preliminary findings and suggested that meaningful effectiveness could be achieved following a single MSC-NTF cell transplantation in the subgroup of patients that excluded slow progressors (submitted for publication). These findings are to be confirmed in a bigger repeat-dose multicenter US phase 3 program.
MicroRNAs (miRNAs) are brief (17-24 nt), single-stranded, endogenous non-coding RNAs that manage gene expression by post-transcriptional silencing and/or mRNA wreckage and can play important regulatory roles in animals plus plants by targeting mRNAs for cleavage or translational repression. miRNAs have been shown to play critical roles in many biological processes, including cell differentiation, cell development, cellular growth and apoptosis, by regulating gene expression by means of either the inhibition of mRNA translation or the induction of mRNA degradation [ 11 – 13 ].
Single miRNA can target several mRNAs, overall targeting approximately 60% of human genetics. They regulate multiple and diverse cellular pathways plus processes in normal and disease situations leading to modifications in cell phenotype.
miRNA act in concert with Argonaute proteins within the RISC complex to suppress translation in a manner which is dependent upon incomplete Watson-Crick base pairing between the so-called ‘ seed’ sequence of the miRNA with complementary sequences in the focus on gene, usually in the 3’ -UTR region of the fully developed message.
This particular study aimed to characterize an MSC-NTF miRNA finger-print by identifying miRNAs that are significantly differentially expressed within MSC-NTF cells compared to the donor-matched MSCs by selecting a solar panel of mi-RNAs to monitor cell differentiation and performance, for use as release criteria, and as an in-vivo identification assay.