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OBJECTIVE: To identify cerebrospinal fluid (CSF) biomarkers of clinical response to intrathecal (IT) mesenchymal stem cell-neural progenitor (MSC-NP) treatment in patients with progressive multiple sclerosis (MS).
BACKGROUND: Limited therapeutic options are available to treat the neurologic disability associated with progressive MS. To address this unmet need, a phase I clinical trial was conducted to evaluate safety, tolerability, and efficacy of a novel cellular therapy utilizing autologous bone marrow mesenchymal stem cell-derived neural progenitors (MSC-NP) administered intrathecally (IT) into patients with progressive MS. Efficacy data from the clinical trial suggests that treatment with MSC-NPs results in improved motor strength and bladder function in MS, despite established disability prior to the treatment. Pre-clinical studies have described the trophic and immunomodulatory effects of MSCNPs both in vitro and in the EAE animal model of MS.
DESIGN/METHODS: MSC-NPs were isolated and expanded from bone marrow of MS patients. Expression of candidate trophic and immunomodulatory factors were analyzed by quantitative PCR. Secreted protein levels in conditioned media were quantitated by ELISA and by luminex assays. To explore whether the candidate MSC-NP factors could serve as biomarkers of therapeutic response, we collected and banked cerebrospinal fluid (CSF) from clinical trial patients before and after intrathecal treatment with autologous MSC-NPs.
RESULTS: Trophic factors including HGF, VEGF and SDF-1 were secreted at high levels by MSC-NPs and were increased in CSF from MSC-NP-treated patients. In addition, CSF levels of neurodegenerative biomarkers including neurofilament light and heavy were reduced in response to IT-MSC-NP treatment, notably in patients with elevated pre-treatment levels of these biomarkers. CSF levels of CCL2 and CXCL12 also showed significant changes associated with clinical response to IT-MSC-NP treatment.
CONCLUSION: These results elucidate the trophic mechanisms of action of MSC-NPs and identify novel biomarkers of stem cell-mediated neural repair.