Designer DNA drug therapy for human neurodegenerative disease
The genes whose mutation causes neurodegenerative disease are widely expressed within neurons and non-neurons of the nervous system, producing misfolded proteins that induce cellular stress not only within the most vulnerable neurons but also within their partner neurons and supporting glia. Sustained gene silencing within neurons and non-neurons throughout the nervous system has been achieved using a clinically feasible approach either with “designer DNA drugs” or an adenoassociated virus (AAV) encoded shRNA delivered by a novel subpial approach that provides for extensive targeting of upper and lower motor neurons. Single ASO doses have been shown to produce sustained suppression of the target gene (mediated by catalytic degradation of the RNA intermediate copied from that gene). In rodents, this approach has slowed disease progression in genetic mimics of inherited ALS and has produced prolonged, partial disease reversal in models of Huntington’s disease. A similar designer DNA drug has successfully corrected an error in the assembly of an RNA intermediate, thereby restoring production of the gene product whose absence is the cause of spinal muscular atrophy (SMA), one of the most abundant inherited diseases of children. For the most frequent genetic cause of both ALS and the second most frequent dementia (frontal temporal dementia – FTD), single dose administration of a designer DNA drug has reduced the synthesis of the toxic product of the mutated gene and prevented age-dependent cognitive disease. Multiple clinical trials to suppress genes contributing to ALS (caused by SOD1 and C9orf72), Huntington’s, and Alzheimer’s diseases are now underway, and trials in Parkinson’s and a set of ataxias are scheduled to start in 2020. Lastly, designer DNA drugs can also be used to produce “identify theft”: the direct conversion of astrocytes into new neurons to replace those lost to neurodegenerative disease, an approach that in mice has successfully produced new dopamine-synthesizing neurons that reverse chemically induced Parkinson’s disease.