CRISPR/Cas9 Edited sRAGE-MSCs Protect Neuronal Death in Parkinson’s Disease Model

Abstract

Background and Objectives Parkinson’s disease (PD) is a fatal and progressive degenerative disease of the nervous system. Until recently, its promising treatment and underlying mechanisms for neuronal death are poorly understood. This study was investigated to identify the molecular mechanism of neuronal death in the substantia nigra and corpus striatum of PD. Methods The soluble RAGE (sRAGE) secreting Umbilical Cord Blood—derived Mesenchymal Stem Cell (UCB-MSC) was generated by gene editing method using clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9). These cells were transplanted into Corpus Striatum of rotenone-induced PD animal models then behavioral test, morphological analysis, and immunohistochemical experiments were performed to determine the neuronal cell death and recovery of movement. Results The neuronal cell death in Corpus Striatum and Substantia Nigra was dramatically reduced and the movement was improved after sRAGE secreting UCB-MSC treatment in PD mice by inhibition of RAGE in neuronal cells. Conclusions We suggest that sRAGE secreting UCB-MSC based therapeutic approach could be a potential treatment strategy for neurodegenerative disease including PD.

CRISPR/Cas9-mediated gene editing induces neurological recovery in an A53T-SNCA overexpression rat model of Parkinson’s disease

“…49,50 A few papers suggested PD animal model treatment methods; however, all of them applied CRISPR to individual cells as an ex vivo treatment technique. 51,52 Invariably, there are no reports of successful in vivo treatments by delivering CRISPR directly to animals with PD. Our study overcomes several difficulties and demonstrates the possibility of familial PD treatment for the first time in an animal model applying CRISPR to knock out the A53T-SNCA gene in vivo, the direct cause of familial PD.…”

Strategies to Potentiate Paracrine Therapeutic Efficacy of Mesenchymal Stem Cells in Inflammatory Diseases

“…For instance, Hu et al have represented a concept of CRISPR-based cell immortalization strategy for mouse MSCs by introducing simian virus SV40 large T antigen into an intrinsic safe harboring site at Rosa26 locus [ 125 ]. In other reports, CRISPR/Cas9 construct was simultaneously delivered with the AAV vector then gene construct that encodes beneficial protein was knock-in into the AAV-specific safe locus such as AAVS1 [ 126 , 127 ]. This AAV-CRISPR/Cas9 genetic engineering platform can induce the stable overexpression of therapeutic factors in MSCs in a relatively simple and safe way.…”

Functional enhancement strategies for immunomodulation of mesenchymal stem cells and their therapeutic application

“…Hu et al demonstrated that CRISPR/Cas9-induced knockout of Keap1 improved anti-oxidation in AT-MSCs [ 63 ]. Introduction of CRISPR/Cas9-edited sRAGE secreting UCB-MSCs reportedly alleviated neuronal degeneration and improved homing to the lesion in Parkinson’s disease animal mice [ 64 ].…”