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Claire D. Clelland, Roger A. Barker and Colin Watts

in treating HD. Disease-modifying therapies—for example, small interfering RNA, pharmacological intervention, and modulation of autophagy—target pathogenic pathways, whereas cell replacement therapies attempt to replace dysfunctional or dying cells primarily through transplantation ( Fig. 2 ). Cell therapy strategies in HD have traditionally been aimed at replacing or protecting cells lost during the course of the disease and thereby preventing or retarding disease progression. Current work in HD cell therapy is broadly classified into 1 of 3 aims: 1) to harness

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Matthew T. Harting, James E. Baumgartner, Laura L. Worth, Linda Ewing-Cobbs, Adrian P. Gee, Mary-Clare Day and Charles S. Cox Jr.

shown to be rich in MSCs. 63 Given the fact that these tissues are a readily available source of cells, they may prove a valuable niche for cell isolation. Cell Therapy: Possible Mechanisms of Action The interactions of transplanted cells and the recipient organism or specific tissue are poorly understood. Significant investigation into potential mechanisms of action that may lead to functional recovery is yielding valuable insight ( Table 1 ). Although recent skepticism has been expressed, differentiation into local–regional cell types and supporting cell

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Antos Shakhbazau, Chandan Mohanty, Ranjan Kumar and Rajiv Midha

extracellular matrix, cell adhesion molecules, and trophic factors. 8 , 44 The therapeutic potential of autologous Schwann cells can be limited by lengthy expansion and the need to sacrifice a healthy nerve, resulting in neuropathic pain and donor site morbidity, and several groups have succeeded in deriving Schwann cells from bone marrow mesenchymal stem cells, adipose stem cells, and skin precursor (SKP) cells. 2 , 9 , 10 , 17 , 21 , 26 , 42 Prior in vivo experiments from our group and others show some histological improvement after stem cell/Schwann cell therapies

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Matthew T. Harting, Fernando Jimenez, Hasan Xue, Uwe M. Fischer, James Baumgartner, Pramod K. Dash and Charles S. Cox Jr.

C ell therapy has garnered significant interest as a treatment strategy for a wide range of diseases over the last decade. Heart disease, peripheral vascular disease, bone disease, cancer, hepatic disease, and neurological disease have all been the focus of promising cell therapy breakthroughs. 7 , 15 , 23 , 24 , 34 , 40 , 48 Traumatic brain injury is one area in which positive preclinical evidence has led to the initiation of early clinical trials ( ). Although cell therapy has been hailed as one of the next frontiers in modern

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Michael C. Jin, Zachary A. Medress, Tej D. Azad, Vanessa M. Doulames and Anand Veeravagu

phases. Primary injury refers to the initial shearing or compression of the spinal cord tissue. The mechanical force of the primary injury causes hemorrhage, disruption of cell membrane integrity, and ion and neurotransmitter imbalance that immediately compromises neural function. Secondary injury pertains to the progressive inflammatory, ischemic, and apoptotic cascade that follows the initial mechanical assault. 52 Stem cell therapies for SCI seek to minimize the spread of secondary injury, augment the function of remaining cell populations, and facilitate

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Olle Lindvall and Peter Hagell

Clinical studies involving intrastriatal transplantation of embryonic mesencephalic tissue in patients with Parkinson disease (PD) have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine release and movement-related frontal cortical activation, and produce significant symptomatic relief. In the most successful cases, patients have been able to withdraw from levodopa treatment after undergoing transplantation and resume an independent life. There are, however, several problems linked to the use of primary embryonic tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients; 2) variability of functional outcome (major improvement in some and modest if any clinical benefit in others); and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in the treatment of PD. For the development of a clinically useful cell therapy we need to define better criteria for patient selection and how graft placement should be optimized in each individual. Most importantly, we need to generate large numbers of viable dopamine neurons in preparations that are standardized and quality controlled. Stem cells could be useful as an unlimited source of dopamine neurons. Thus far, neurons with at least some dopaminergic characteristics have been generated from stem cells. In most cases, however, their survival after grafting in animals has been poor, and it is also unclear if they function as normal dopamine neurons. Several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.

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Moneeb Ehtesham, Charles B. Stevenson and Reid C. Thompson

The prognosis for patients with malignant glioma, which is the most common primary intracranial neoplasm, remains dismal despite significant progress in neurooncological therapies and technology. This is largely due to the inability of current treatment strategies to address the highly invasive nature of this disease. Malignant glial cells often disseminate throughout the brain, making it exceedingly difficult to target and treat all intracranial neoplastic foci, with the result that tumor recurrence is inevitable despite aggressive surgery and adjuvant radiotherapy and/or chemotherapy. The use of neural stem cells (NSCs) as delivery vehicles for tumor-toxic molecules represents the first experimental strategy aimed specifically at targeting disseminated tumor pockets. Investigators have demonstrated that NSCs possess robust tropism for infiltrating tumor cells, and that they can be used to deliver therapeutic agents directly to tumor satellites, with significant therapeutic benefit. With the aim of developing these findings into a clinically viable technology that would not be hindered by ethical and tissue rejection–related concerns, the use of adult tissue–derived stem cells has recently been explored. These technologies represent important progress in the development of a treatment strategy that can specifically target disseminated neoplastic pockets within the brain. Despite encouraging results in preclinical models, however, there are significant impediments that must be overcome prior to clinical implementation of this strategy. Key among these are an inadequate understanding of the specific tropic mechanisms that govern NSC migration toward invasive tumor, and the need to refine the processes used to generate tumor-tropic stem cells from adult tissues so that this can be accomplished in a clinically practicable fashion. Despite these limitations, the use of stem cell therapies for brain tumors holds significant promise and may emerge as an important therapeutic modality for patients with malignant glioma.

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Nachshon Knoller, Gustavo Auerbach, Valentin Fulga, Gabriel Zelig, Josef Attias, Ronit Bakimer, Jonathan B. Marder, Eti Yoles, Michael Belkin, Michal Schwartz and Moshe Hadani

-term adverse effects on the macrophage treated animals were observed (reported to the Food and Drug Adminstration under Investigational New Drug application No. 8427). Based on these findings, a cell therapy is being developed that consists of autologous skin coincubated macrophages. Unlike single-molecule therapy, autologous macrophage therapy is intended to exploit the numerous activities that are characteristic of these cells, including the clearance of tissue debris from the lesion site, the secretion of protective and healing molecules, and the modulation of the other

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Douglas Kondziolka, Lawrence Wechsler, Elizabeth Tyler-Kabara and Cristian Achim

Cellular therapy has been evaluated in small animals, subhuman primates, and now humans for the potential repair of brain injury due to stroke. Experimental striate stroke models have proven useful for the purpose of evaluating different treatment paradigms. Early clinical trials involving neuronal transplantation in patients suffering motor-related stroke in the basal ganglia region have begun.

This research will be described in this report.

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John F. Alksne