Cell Therapy for Parkinson's Disease: New Hope from Reprogramming Technologies.

Volume 6, Number 6; 499-503, December 2015 http://dx.doi.org/10.14336/AD.2014.1201 Review Article Cell Therapy for Parkinson’s Disease: New Hope from Reprogramming Technologies Zhiguo Chen 1,2,3,* 1 Cell Therapy Center, Xuanwu Hospital, Capital Medical University, and Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China 2Center of Neural Injury and Repair and 3Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China [Received September 14, 2014; Revised December 1, 2014; Accepted December 1, 2014] ABSTRACT: Parkinson’s disease (PD) is a neurodegenerative disease with the major pathology being the progressive loss of dopaminergic (DA) midbrain neurons in the substantia nigra. As early as in the 1980s, open-label clinical trials employing fetal ventral mesencephalon (fVM) tissues have demonstrated significant efficacy for PD treatment, which led to two NIH-sponsored double-blind placebo-controlled clinical trials. However, both trials showed only mild outcome. Retrospective analysis revealed several possible reasons that include patient selection, heterogeneity of grafts, immune recognition of grafts, lack of standardization of transplantation procedure and uneven distribution of grafts. Recent years have seen advances in reprogramming technologies which may provide solutions to the problems associated with fVM tissues. Induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) hold promise for generating clinical grade DA neural cells that are safe, homogeneous, scalable and standardizable. These new technologies may bring back clinical trials using cell therapy for PD treatment in the future. Key words: cell therapy, Parkinson’s disease, reprogramming, dopaminergic neurons, clinical trials Parkinson’s disease (PD) is the second most common neurodegenerative disease in people over 60 years old [1, 2]. The major pathology of PD is the progressive degeneration of dopaminergic (DA) neurons located at the substantia nigra in midbrain, which send axonal projections to striatum and are involved in the circuits controlling motor functions. In addition to motor symptoms caused by degeneration of DA neurons, many PD patients also present with non-motor symptoms, such as cognitive impairment and mood problems [3]. To date, no disease modifying treatments exist in clinics. The current treatments mostly target the symptoms only. Pharmaceutical drugs, such as levodopa, catechol-O-methyl transferase, and monoamine oxidase inhibitors, aim at replenishing or stabilizing dopamine supply in striatum; Deep brain stimulation (DBS) normally works by electrically lesioning subthalamic nucleus (STN) or globus pallidus interna (GPi) to increase the collective motor output. However, neither of the above can stop nor reverse the progress of DA neuron degeneration in midbrain. Other emerging treatments that have gone through clinical trials include gene therapies and cell transplantation therapies. Through gene therapy, viral vectors encoding GAD, neurotrophic/growth factors, or enzymes sufficient for production of dopamine have been trialled or still underway [4-9]. In this short review, I will focus more on the cell therapy aspect of PD treatment. *Correspondence should be addressed to: Zhiguo Chen, Ph.D., Professor, Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. Email: ISSN: 2152-5250 499 Z. Chen Human fetal ventral mesencephalon (fVM) tissue transplantation for PD treatment In PD patients, the degenerating neurons are restricted in space and cell type – mainly DA neurons at the substantia nigra are injured; this feature attracts the interest of cell biologists and makes PD a feasible disease for cell transplantation therapy. In adult brain, it is very difficult to reconstruct the nigro-striatal circuit. DA neurons placed at the substantia nigra lack the appropriate microenvironment to send their axons into the striatum. Instead, dopamine-producing tissues/cells were engrafted at striatum in order to replenish dopamine supply. Since the 1980s, various cell sources have been tested, which include autografts of adrenal medulla, sympathetic ganglion, carotid body-derived cells, xenografts of fetal porcine ventral mesencephalon, and allografts of human fetal ventral mesencephalon (fVM) tissues [1, 10-14]. Among them, the most successful were the studies employing fVM tissues. In the initial open-label trials, PD patients receiving fVM tissues showed steady improvement in symptoms and survival of functional grafts as evidenced by PET imaging [14-20]. The encouraging results led to two double-blind clinical trials sponsored by National Institutes of Health (NIH) in the United States [21, 22]. Disappointingly, both trails failed to meet the primary end points. Although a subpopulation of patients showed significant improvement, as a whole, no statistical significance was observed. Even worse was that, for the first time, graft-induced dyskinesias (GID) was found in 15-50% of the engrafted patients. Since then, clinical trials using fVM tissues/cells have come to a standstill. Careful retrospective analysis revealed several possible reasons for the mild outcome. The subpopulation that responded well to fVM transplantation were relatively younger patients at an early stage of PD who remained responsive to levodopa treatment [23, 24]. It seems certain numbers of remaining endogenous nigrostriatal innervations are necessary for fVM grafts to exert significant functions. Another possible reason was the immune recognition of incoming grafts. Although the brain is a relatively immune privileged organ, allogeneic neural grafts may still elicit innate and adaptive immune signaling, which can influence transplantation outcomes [25-27]. In one of the two double-blind clinical trials, immunosuppressant cyclosporine was administered two weeks before and through six months after transplantation [21]. Patients experienced improvement in motor functions until the withdrawal of immunosuppression, at which time the patients’ symptoms started to deteriorate. The coincidence in timing suggests that allograft-induced immune recognition plays an important role. The mechanisms underlying GID still remain unclear. One possibility was that the uneven distribution of grafts Cell therapy for Parkinson’s Disease resulted in unbalanced innervations and formation of “hot spots”, leading to pulsatile stimulations. Another possibility was that midbrain grafts were heterogeneous; they contained not only DA neurons but also other neuronal subtypes, such as serotonergic neurons. Serotonergic neurons can convert levodopa to dopamine and release it as a “false” transmitter. However, serotonergic neurons lack the autoregulatory mechanism to control the extracellular level of dopamine; this “uncontrolled” release of dopamine may contribute to levodopa-induced dyskinesia, but cannot explain why GID still e (...truncated)