The development of stem cell-based regenerative medicine is rapidly advancing and has great potential to treat human diseases intractable to conventional medicine. Major hurdles, however, still hinder the widespread clinical application of cell-based therapeutics, including immune rejection of allogeneic cells and the risk of teratoma formation and malignant growths. Employinggenome-editing strategies, weaddressed the issues of safetyand immune-tolerabilitythrough developing the SafeCell(CS) and induced-allograft tolerance (iACT) systems, respectively.The SC system inserts a suicide gene into a cell division essential locus, allowing selective elimination of proliferative cells through the administration of a pro-drug, whilst also protecting the suicide gene from inactivation. The iACT system incorporates combined overexpression of immunomodulatory genes involved in inducing immune-tolerance in allogeneic transplantation settings. Here, we sought to demonstrate the application of our SC and iACT systems for treatment of neurological diseases. By incorporating expression of enhanced firefly luciferase, we used bioluminescence imaging to monitor the survival and proliferation of gene-edited mESCs after stereotaxic injection into the mouse brain. Here we show that SC mESCs canengraft, proliferate and differentiate in the mouse brain following injection. The proliferative component of the graft can be eliminated followingadministration of pro-drug. When injected subcutaneously in allogeneic mice, theiACTsystem has been proven to prevent rejection and allow long-term survival of allografts. We provide additional evidence that after stereotaxic injection into the brain, the iACT system protects the allograft against rejection during neuroinflammation.If validated, our approach harnessing the SC and iACT technologies would contribute to the development of safe, immune tolerant and more effective cell therapies for treating neurological disease.