John Tuddenham, Violaine Harris, PhD, Tamara Vyshkina and Saud Sadiq, MD
Presented at the International Society of Stem Cell Research (ISSCR) annual meeting, held June 22-25, 2016 in San Francisco, CA, USA
Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the CNS. Patients with progressive MS experience a steady worsening of neurologic function attributed to chronic demyelination and axonal loss. There are limited therapeutic options available to treat the neurologic disability caused by progressive MS. To address this unmet need, we are currently conducting a Phase I FDA-approved trial to evaluate safety, tolerability, and preliminary efficacy of a novel cellular therapy utilizing autologous bone marrow MSC-derived neural progenitors (MSCNP) administered intrathecally into patients with progressive MS. Preliminary efficacy data from the clinical trial suggests that treatment with MSCNPs results in improved motor strength and bladder function in a subset of patients, despite their 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. The purpose of the current study is to elucidate the therapeutic mechanism of action of MSCNPs through the identification of biological factors that correlate with clinical response. MSCNPs were isolated and expanded from bone marrow of MS patients. Analysis of gene expression of MSC-NPs demonstrated upregulation of a panel of candidate trophic and immunomodulatory factors, including HGF, IGF, LIF, VEGF, IL-11, and TGF-beta. Secreted protein levels in MSCNP conditioned media were quantitated by ELISA and by luminex assays and correlated with promotion of neurogenesis/oligodendrogenesis in an in vitro co-culture assay with neural stem cell lines. To explore whether the candidate MSCNP factors could serve as biomarkers of therapeutic response, we collected and banked cerebrospinal fluid from clinical trial patients at baseline and after each intrathecal treatment with autologous MSCNPs. Multiple factors, including HGF, were detectable in cerebrospinal fluid and correlated with clinical responses. These results elucidate the trophic mechanisms of action of MSCNPs and identify novel biomarkers of stem cell-mediated neural repair.