Mol Neurobiol (2012) 45:87–98 For any planned delivery method, it will be important to provide a precise and quantitative evaluation of BDNF protein level in the human CNS, perhaps by conducting a spinal tap after the therapy. Methods for precise quantitation of BDNF have been described by Zuccato et al. [61, 62]. BDNF is a complex protein that could have unwanted side effects if expressed at very high levels. It will also be important to regulate BDNF levels using an inducible promoter system, since transgenic mouse models have shown that high levels of BDNF overexpression in the brain can interfere with normal brain function by causing learning impairments and increased excitability [63]. Discussion of potential therapeutic approaches in the context of MSC-based treatments and growth factor delivery for HD is presented in this review. Huntington’s Disease HD is an incurable inherited genetic disorder where the condition of the patients inexorably worsens and their prognosis is eventual death, following decline in control of emotion, movement, and cognition. The pathology of HD is caused by a variable sized polyglutamine expansion of the protein product of the huntingtin (HTT) gene. Multiple disease mechanisms have been described for HD neuro- degeneration and are currently under investigation in the search for therapeutics. HD is a challenging disease to treat. Not only do the affected, dying neurons need to be rescued or replaced, but the levels of the toxic mutant protein must also be diminished to prevent further neural damage and to halt progression of the movement disorders and physical and mental decline associated with HD. The best hope for halting HD progression is to reduce or eliminate the mutant Htt protein in the affected cells [64, 65]. Small interfering RNAs (siRNA) have been shown to be effective at reducing Htt levels and ameliorating disease symptoms in animal models [66, 67]. Exciting new data shows that the mutant HTT mRNA can be specifically silenced by targeting conserved single nucleotide poly- morphisms in the mutant allele, while sparing the transcript produced by the normal allele [68–70]. The challenge for this technology is to deliver the siRNA into the human brain in a sustained, safe, and effective manner. Our group is currently funded by the California Institute for Regenerative Medicine to develop an siRNA delivery system using human MSC as the “production factories” in the brain. Safety and efficacy studies are ongoing [55]. Many studies have demonstrated the safety and efficacy of MSC injection into the brain and central nervous system. Lescaudron and colleagues [71] transplanted autologous bone marrow stem cells into the damaged striatum of the rat HD model and found that the transplant significantly 91 reduced working memory deficits. The transplanted MSC remained undifferentiated, but exerted trophic effects on the injured tissue. Bantubungi et al. [72] found that the lesioned environment of the striatum favored the proliferation and intralesional distribution of MSC. Several groups have shown that striatal atrophy in models of HD is accompanied by the subsequent enlargement of lateral ventricles [73, 74]. The reduction in volume of the lateral ventricle can thus be a good indicator of repair in HD correction studies. Amin et al. [73] demonstrated that after MSC implantation into the striata of rats with a unilateral damage model of HD, striatal atrophies were significantly reduced. Consequently, the volume of the lateral ventricle returned to a significantly smaller size, approaching the normal contralateral ventricle. Their results demonstrated the potential for MSC in the treatment of microanatomical defects in the motor disorders of HD. Groups who have evaluated the impact of intrastriatal transplantation of MSC in rodent models of HD are summarized in Table 1 [73, 75–82]. Some groups had hoped to observe MSC becoming neurons after transplan- tation. However, as discussed above, although some neuronal markers can be observed on transplanted MSCs due to their propensity for “sharing” membrane and cytoplasmic markers and natural expression of a number of traditionally neural markers like nestin [46], bona fide transdifferentiation into functional neurons has not been convincingly demonstrated. In contrast to “transdifferentia- tion” to neural cells, through the ability of MSC to secrete neurotrophic factors, reduce inflammation, reduce apoptosis, enhance axonal extension, and reduce reactive oxygen species, significant positive effects were seen in alleviating HD progression in the studies listed. Data suggest that MSC implantation into the striatum can potentially delay the unrelenting loss of medium spiny neurons in HD. An important factor to consider is that the MSC implanted at adjacent sites have the capacity to migrate into the most damaged areas in response to stress or death of medium spiny neurons, which are lost in HD. MSC are known to migrate robustly in the brain, in response to injury. Delcroix et al. [83] demonstrated that iron nanoparticle-labeled MSC migrated from an implanta- tion site in the subventricular zone microenvironment toward the olfactory bulb through the rostral migratory stream only when a mechanical lesion of the olfactory bulb was performed. They confirmed the known potential of MSC to migrate toward areas of damage, even over a great distance in the brain. The migratory capacity of MSC was further examined by transplantation of the cells a distance from a quinolinic acid (QA)-induced striatal lesion, a rat model for Huntington’s disease [82, 84]. Migration was monitored using MRI scans followed by histology. The engrafted MSC were shown to have migrated a great