94 A pilot trial using either intravenous- or intrathecal- injected MSC has been conducted by Karussis and colleagues in 12 patients diagnosed with untreatable neurodegenerative diseases—ALS or multiple sclerosis [102]. Their intent was to demonstrate the safety of the delivery methods and treatment with autologous MSC. They initiated the pilot trial after in vitro and pre-clinical investigations had demonstrated immunomodulatory effects of MSC with suppression of self-reactive T lymphocytes. In addition, animal studies in mice with chronic progressive experimental autoimmune encephalomyelitis had mitigation of their clinical course accompanied by histopathological evidence of neuroregeneration following IC and IV injection of MSC [103]. Their study was extended to include 10 ALS and 10 MS patients showing proof of concept that both delivery methods were feasible and safe. They are currently conducting a larger phase I/II trial delivering autologous MSC as treatment in patients with severe refractory MS [104]. Additional case reports and a small pilot study including 10 patients with multiple sclerosis treated with autologous MSC have been con- ducted with intriguing results (Bonab et al. [105–107]). Currently, there are at least four clinical trials being conducted at centers in UK, Israel, Spain and the USA Mol Neurobiol (2012) 45:87–98 evaluating the safety and efficacy of bone-marrow-derived MSC in treatment of MS. Direct injection of MSC into the injured region of the brain during surgery following traumatic brain injury (TBI) has also been performed without adverse events. Seven TBI patients each received up to 109 expanded MSC during the cranial repair operation [108]. Patients were followed for 6 months and demonstrated significant improvements in neurologic function. Placebo-controlled trials for MSC injection into the CNS for TBI and stroke, as well as spinal cord injury and neurodegenerative disorders, are currently ongoing in countries outside of the USA (clinicaltrials.gov). No adverse events have been reported from these studies. As one example, Venkataramana et al. [109] recently reported safety data from an open label phase I clinical trial where autologous bone-marrow-derived MSC were transplanted into the striata of patients with advanced PD. No adverse events occurred and possible clinical improvement was observed. Clinical trials of an MSC-like multipotent cellular product, Multistem [110, 111], has been approved by the FDA to treat stroke in the USA, by the company Athersys. Celgene is approved for a multicenter phase II clinical trial to use placental-derived MSC for treating stroke, and San-Bio is conducting a phase I trial of gene-modified Fig. 2 Schema of proposed human MSC therapy for neurodegenerative disease. Bone marrow is harvested from a normal, qualified donor. MSC are expanded and transduced with viral vectors in the good manufacturing practice facility using qualified reagents and well-established standard operating procedures. The transduced cells are expanded, tested extensively, and banked. Following FDA clearance of the phase 1 clinical trial, the qualified cells will be implanted near the affected portion of the brain in symptomatic HD patients. MSC will be thawed, tested, and infused under MRI guidance by an experienced Neurorestorative Therapy Team. Patients will then be followed by experienced clinicians in the movement disorders clinic for evaluation of potential neurorestorative effects: slowing of disease progression as measured by total functional capacity score and delay in volumetric MRI changes known to occur in HD. Potential clinical improvement in severity of movement disorders and cognitive impairment as measured by the Unified HD Rating Scale (UHDRS) and a battery of cognitive tests will be monitored