C32 Designer DNA drug therapy for human neurodegenerative disease

27-11-2019

MNDA SYMPOSIUM PERTH DEC19 PRESENTATIONS

Session 4 Therapeutic strategies

Don Cleveland, USA

Background: The genes whose mutation causes neurodegenerative disease are widely expressed within neurons and non-neurons of the nervous system, producing damage 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 with “designer DNA drugs” (also known as antisense oligonucleotides). Single doses have been shown to produce sustained suppression of the target gene (mediated by catalytic degradation of the RNA intermediate copied from that gene).

This approach has slowed disease progression in inherited ALS caused by mutation in superoxide dismutase (SOD1), with a pivotal Phase III trial now recruiting ALS patients. For the most frequent genetic cause of both ALS and frontal temporal dementia (hexanucleotide expansion in the C9orf72 gene), single dose administration of a designer DNA drug has reduced the synthesis of the toxic product(s) and prevented age-dependent disease in mice.

The designer DNA drug approach can be used broadly in neurodegenerative diseases. A 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.

Designer DNA drug infusion has produced prolonged, partial disease reversal in models of Huntington’s disease, lowered mutant huntingtin in the nervous systems of human patients, and is now in a large Phase III trial. A clinical trial is also underway to suppress synthesis of tau in Alzheimer’s disease. Trials in Parkinson’s disease are anticipated to initiate in 2020. 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 initial example of this has successfully produced new dopamine-synthesizing neurons that reverse chemically induced Parkinson’s disease in mice. Extension of this approach to generate replacement neurons in other neurodegenerative conditions, including ALS, are now underway.

Source: Abstract Book symposium Perth