MODULATION OF CSF miRNAs IN ALS PHASE 2 STUDY PARTICIPANTS TREATED WITH MSC-NTF CELLS (NUROWN®) (S25.005)

Objective: To measure cell-secreted and ALS-related miRNA expression in the CSF pre- and post-single intrathecal MSC-NTF cell transplantation and to evaluate their correlation with ALS treatment outcomes. Background: MSC-NTF cells (NurOwn ® ) are autologous bone-marrow derived mesenchymal stem cells (MSC) that secrete high levels of neurotrophic factors (NTFs). miRNAs are small non-coding RNAs that regulate a wide variety of biological processes via RNA-dependent post-transcriptional silencing mechanisms. We have demonstrated that MSC-NTF cells express a unique miRNA profile compared to undifferentiated MSC that may regulate neurogenesis and neuroinflammation. MSC-NTF cells were administered by the intrathecal route to participants in a US Phase 2 ALS multicenter double-blind placebo-controlled trial to evaluate their safety and efficacy (NCT02017912) and CSF biomarkers (NTFs, cytokines and miRNA). Design/Methods: CSF was collected prior to, and two weeks after intrathecal MSC-NTF cells transplantation. After measurement of NTFs and cytokines, CSF miRNAs were analyzed in pools of three homogeneous groups of responders; non-responders and placebo participants using the Exiqon platform. Results: The expression of miR-34a, miR-132, miR-19, miR-376a and miR-146a-5p, that are highly expressed in MSC-NTF cells, were found to be increased 2-weeks post treatment in MSC-NTF treated but not placebo participants, suggesting that transplantation was associated with immunomodulatory and neuroprotective effects. CSF miR-34a, miR-376a and miR-132 baseline levels were lower in non-responder as compared to responder participants. Post-treatment CSF miR-146-5p was higher in responders, consistent with the observed decrease in CSF MCP-1. Conclusions: MSC-NTF specific miRNAs were increased in the CSF of treated but not placebo participants 2-weeks post-transplantation, suggesting continued secretory activity of MSC-NTF cells near the site of intrathecal administration. The increase of CSF miR-146 in responders, known to modulate inflammatory responses, and expression of miR-132-3p, enriched in neurons and relevant to ALS pathogenesis, supports the combined immunomodulatory and neuroprotective mechanism of action of MSC-NTF cells. Study Supported by: Brainstorm Cell Therapeutics Ltd. Disclosure: Dr. Aricha has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Brainstorm Cell Therapeutics Ltd. Dr. Kaspi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Brainstorm Cell Therapeutics Ltd. Dr. Cudkowicz has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Windebank has nothing to disclose. Dr. Staff has nothing to disclose. Dr. Owegi has nothing to disclose. Dr. Levy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Brainstorm Cell Therapeutics Ltd. Dr. Lebovits has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Gothelf has nothing to disclose. Dr. Kern has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Brainstorm Cell Therapeutics Ltd.