Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen


Expert Rev Neurother. 2011;11(9):1325-1339. 

In This Article

Induced Pluripotent Stem Cells

Recent success with the generation of human iPSCs has provided great potential in the stem cell field. Takahashi and Yamanaka developed a technique that is based on the reprogramming of cells from fully differentiated tissues into iPSCs, through viral expression of four transcription factors (termed 'reprogramming factors'): OCT4, SOX2, KLF4 and C-MYC.[91] Although further characterization is needed, iPSCs appear to have similar capabilities as ESCs.[61] This discovery suggested that patient-specific stem cell lines could be generated to study patient-specific disease progression and to treat patients with personalized, tissue-matched transplants without immunological complications.[92] However, a major drawback of the iPSC technology is that it requires viral vectors for reprogramming, which can result in residual transgene expression and may cause malignant tumors. iPSCs have great therapeutic potential for PD and other diseases if safer alternatives for reprogramming can be identified. Recently, Soldner and colleagues reported a novel method for creating iPSCs from skin biopsies of idiopathic PD patients, free of reprogramming factors, using Cre-recombinase excisable viruses.[93] Factor-free iPSCs maintain a pluripotent state and show a global gene expression profile more closely related to human ESCs than to iPSCs carrying the transgenes. This result indicates that residual transgene expression in virus-carrying iPSCs can affect their molecular characteristics and that factor-free iPSCs represent a more suitable source of cells.[93] A study by Wernig et al. has shown that mouse fibroblast-derived iPSCs, differentiated into midbrain DA neurons with SHH, FGF8, FGF2 and AA, can functionally integrate in the host striatum of parkinsonian rats and lead to behavioral improvements.[32] However, neuronal overgrowths have been observed, similar to those seen in ESC grafts. The risk of tumor formation by iPSCs is expected to be even higher than that with ESCs, as the reprogramming process involves the regulation of a tumor suppressor gene, p53.[94] Another important issue is that patient-derived iPSCs may carry mutations, polymorphisms or epigenetic marks that could make them more susceptible to develop PD-like features.[2,70,95] iPSCs represent a tremendous discovery, but as shown previously, still have many drawbacks and further investigation is needed before clinical application could be attempted. In line with the induced-cell type approach via reprogramming factors, and trying to circumvent the oncogenic potential of the iPSCs, Vierbuchen et al. have shown that expression of three transcription factors can rapidly and efficiently convert mouse fibroblasts into functional neurons (inducible neuron [iN] cells).[96] The iN cells displayed functional neuronal properties, such as the generation of trains of action potentials and synapse formation. Future studies will be necessary to determine whether iN cells could represent an alternative to generate patient-specific neurons.[96]