PCE 76


  Ischemic stroke is the second leading cause of death and the primary reason for sustained disability worldwide for which no neurorestorative treatment exists. After cerebral ischemia, the ratio between astroglial cells and neurons in the neurovascular unit is disrupted in the perilesional area. We hypothesized that restoring the balance within the neurovascular unit may lead to an enhanced functional recovery after focal ischemia. In previous work we have found that the conversion efficacy of proliferating astrocytes into neurons after cerebral ischemia in young and aged mice is disappointingly low, most likely because the retroviruses carrying the conversion gene are engulfed by phagocytic microglia shortly after intracortical administration (Popa-Wagner et al., Frontiers Aging Neurosci. 2019). In the present project we would like to take advantage of new developments in the field to improve the efficacy of genetic conversion of astrocytes into neurons at the lesion site caused by cerebral ischemia by adopting recently developed innovative technologies using either Adeno-Associated Virus-mediated ectopic expression of the transcription factor NeuroD1 (Nature Comm. 11:1105, 2020) or using CRISP-CasRx technology for successful glia-to-neuron conversion (Cell 181:590, 2020). Given the overwhelming importance of stroke therapy for both patients and society, this approach, if successful, will be a breakthrough in the field.