On the Publication of “Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy (S28. 005),” which was published in the April edition of Neurology!
To develop genome therapy in human DM1 iPS cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy Background: Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the 3′-untranslated region (3’ UTR) of the DMPK gene, for which there is no effective therapy. Human iPS cells hold great promise for regenerative medicine. iPS cells can be generated from somatic cells of the same patient, termed patient-specific iPS cells, which essentially overcome the hurdle of immune rejection of autologous cell transplantation. In order to prevent DM1 stem cells and their progeny from undergoing the same degenerative process after transplantation, modifying the mutant genome to generate healthy DM1 iPS cells would be an important step towards autologous stem cell therapy. Methods: The general approach involves targeted insertion of poly A signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination (HR) triggered by site-specific TALEN-induced double-strand break (DSB). Results: We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. Conclusions: genome therapy by insertion of PASs upstream of the expandedDMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.