Aims

Sustained gene silencing throughout the nervous system has been achieved using “designer DNA drugs”, a.k.a., antisense oligonucleotides or ASOs. ASOs slow disease progression or produce disease reversal in models of inherited ALS and Huntington’s disease, respectively, with pivotal Phase III trials now in progress, as well as trials for C9orf72-mediated ALS/FTD or to suppress tau in Alzheimer’s or LRRK2 or alpha synuclein in Parkinson’s.

Here we show that ASOs can also be used to produce “identify theft”, direct conversion of astrocytes into new functional nigral or hippocampal neurons in a single step by depleting the RNA binding protein PTB.

Methods

Suppression of PTB using a therapeutically viable approach with injection of an antisense oligonucleotide (ASO) into cerebral spinal fluid of healthy adult mice is shown to convert astrocytes into new neurons, especially in the hippocampus.

Results

ASO-mediated suppression of PTB in the brains of aged mice is shown to generate many new hippocampal neurons that are electrically active, send axons into CA3, and receive both inhibitory and excitatory inputs. Suppression of PTB in mice with chemically induced Parkinson’s disease potently reverses disease through converting astrocytes into new substantia nigral neurons to restore striatal dopamine. Using a therapeutically viable injection into cerebral spinal fluid, PTB targeting ASOs drive astrocyte to nigral neuron conversion that mediates reversal of chemically induced Parkinson’s-like disease.

Conclusions

ASO-mediated suppression of PTB may be a generalizable, therapeutically feasible strategy for treating neurodegenerative disorders, including Parkinson’s, Alzheimer’s, and Huntington’s, by converting astrocytes into neuronal replacements for those lost to disease.