Mol Neurobiol (2012) 45:87–98 93 Fig. 1 MSC/BDNF in the brain of an immune deficient mouse. Human mesenchymal stem cells engineered to secrete brain-derived neurotrophic factor (BDNF) and a reporter gene (enhanced green fluorescent protein, or eGFP) were transplanted into the brain of immune-deficient mice using stereotactic injection. Tissues were harvested for assessment of human cell engraftment and biosafety at different timepoints. Shown is engraftment at 6 days post-injection mice. Up-regulation of BDNF in the brains of transgenic rodent models of HD has shown amelioration of the disease phenotype [89]. Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for HD was shown to delay the onset of the motor phenotype [90]. Due to its pro-survival effects in striatal neuropathology, BDNF is a leading candidate for neuroprotective therapies in HD [62, 91, 92]. In transgenic mouse models of HD, there is a significant reduction in the aberrant behavioral phenotype following administration of MSC/BDNF [93]. The Dunbar laborato- ry has shown that MSC, especially those engineered to over-express BDNF, have significant ameliorative effects on disease progression in a transgenic mouse model of HD [93]. These studies have demonstrated that MSC engineered to produce BDNF and implanted into the striata significantly increased time to fall in rotorod testing, demonstrating an increase in coordination and reduction in movement disorders in treated mice during the 13 months of the study. The MSC/BDNF therapeutic also significantly reduced limb clasping, a hallmark behavioral defect in HD mice, over the same time period [93]. A major impediment for the clinical use of neurotrophic factors is their inability to cross the blood–brain barrier in therapeutic amounts. In the quest to begin translating promising studies such as those published by Dey et al. [93] to the clinic, we have shown biosafety of intracranial administration of MSC in long-term rodent and non-human primate models. Our group uses human MSC as safe and long-lived delivery factories for cytokines and growth factors [2, 17, 94]. We are currently evaluating the safety and efficacy of MSC engineered to secrete BDNF in peripheral tissues and in the brain to enhance neuro- restorative capacity in HD (Fig. 1). The use of MSC to deliver factors, both through their own innate responses and through engineering, has benefits beyond direct protein administration. Transplanted MSC can provide sustained and long-term delivery of factors at supraphysiological levels, as we and others have shown over the past two decades [17, 19, 20, 95–98]. Using immune-deficient mouse models, we have recovered human MSC from numerous organs at timepoints from 1 to 18 months post-transplantation, with continued expression of the gene product [16, 17, 19, 94, 95, 97, 99]. We also performed a decade-long biosafety study to demonstrate that genetically engineered human MSC are safe, with no adverse events ever having been observed in vivo [18]. Efforts from our group and others are currently evaluating the effects of BDNF expression from human MSC implanted into the striata of HD mice. Taken together, the data discussed in the current review provide support for the potential for MSC to deliver augmented neurotrophic support. Clinical Trials of MSC for Neural Repair The ability of MSC to secrete factors to decrease motor neuron death when implanted into the CNS of ALS patients was assessed in a human clinical trial [100, 101]. Ten patients with ALS who had severe functional impairment of their legs were enrolled in the MSC clinical trial with no adverse events. Autologous MSC were isolated from the patient’s own bone marrow and expanded using good manufacturing practice conditions. Expanded MSC were suspended in autologous cerebrospinal fluid (CSF) and transplanted into the recipient’s spinal cord at a high thoracic level. No immediate or delayed transplant- related toxicities were observed. Patients were regularly monitored before and after transplantation using clinical, psychological, neuroradiological, and neurophysiological evaluations. Three months after cell implantation, a trend toward slowing of the decline in muscular strength was observed in the legs of four of the first seven patients treated. No significant acute or late side effects were evidenced, and four of the patients showed significant slowing of disease progression [101]. These studies demonstrated that MSC infusion into the cerebro- spinal fluid can be tolerated without adverse events in patients with ALS [101]. A phase II clinical trial using MSC is underway in Europe, and the FDA has recently approved a phase I trial of MSC delivery to the CNS for ALS in the United States.