Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB

• Published in: Nature neuroscience 2021-08, Vol.24 (8), p.1089-1099
• Main Authors: Maimon, Roy, Chillon-Marinas, Carlos, Snethlage, Cedric E., Singhal, Sarthak M., McAlonis-Downes, Melissa, Ling, Karen, Rigo, Frank, Bennett, C. Frank, Da Cruz, Sandrine, Hnasko, Thomas S., Muotri, Alysson R., Cleveland, Don W.
• Format: Article
• Language: English
• Subjects: 631/378; 631/378/368/2431; Aging; Amyotrophic lateral sclerosis; Animal Genetics and Genomics; Animals; Antisense oligonucleotides; Antisense therapy; Behavioral Sciences; Binding proteins; Biological response modifiers; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain research; Cellular Reprogramming - physiology; Cerebrospinal fluid; Circuits; Degeneration; Dentate gyrus; Dentate Gyrus - cytology; Dentate Gyrus - physiology; Disease; DNA biosynthesis; Ependymoglial Cells - cytology; Ependymoglial Cells - physiology; Gene expression; Genetic aspects; Glial cells; Glial fibrillary acidic protein; Injection; Maturation; Medical research; Mice; Mimicry; Nervous system; Neurobiology; Neurodegenerative diseases; Neurogenesis; Neurogenesis - physiology; Neuronal-glial interactions; Neurons; Neurons - cytology; Neurons - physiology; Neurosciences; Oligonucleotides; Oligonucleotides, Antisense; Physiological aspects; Polypyrimidine Tract-Binding Protein - antagonists & inhibitors; Proteins; Stem cells; Young adults
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-021-00864-y

Methods to enhance adult neurogenesis by reprogramming glial cells into neurons enable production of new neurons in the adult nervous system. Development of therapeutically viable approaches to induce new neurons is now required to bring this concept to clinical application. Here, we successfully generate new neurons in the cortex and dentate gyrus of the aged adult mouse brain by transiently suppressing polypyrimidine tract binding protein 1 using an antisense oligonucleotide delivered by a single injection into cerebral spinal fluid. Radial glial-like cells and other GFAP-expressing cells convert into new neurons that, over a 2-month period, acquire mature neuronal character in a process mimicking normal neuronal maturation. The new neurons functionally integrate into endogenous circuits and modify mouse behavior. Thus, generation of new neurons in the dentate gyrus of the aging brain can be achieved with a therapeutically feasible approach, thereby opening prospects for production of neurons to replace those lost to neurodegenerative disease. Maimon et al. demonstrate a therapeutically viable approach, single-dose injection of a DNA drug to suppress synthesis of PTB, to generate new neurons in the aged mouse hippocampus and enhance memory after their integration into endogenous circuits.