From Bench to Bedside: Antisense Therapy
Dec 20, 2019 12:00 AM
The neurology world has a new class of molecules in its armamentarium against neurological diseases. These novel drugs are called antisense oligonucleotides (ASOs).
What are ASOs?
ASOs are made up of modified DNA/RNA-like nucleotide bases, usually including 18 to 20 nucleotides. These oligonucleotide sequences are designed so that their bases can pair (hybridize) with specific messenger RNAs (mRNAs), the blueprints to making their respective proteins. Depending on specifics of ASO design this base pairing can lead to the destruction of harmful mRNAs or the change of the composition of mRNA parts (splicing). Modifications to the ASO bases enhance target stringency (accuracy) and minimize degradation, making ASOs long lasting.
Clinicians and scientists in the Department of Neurology are currently working on all stages of preclinical ASO development in cells and animal models all the way to testing ASOs for the treatment of patients. Daniel Scoles, PhD and Stefan Pulst, MD are developing ASOs that target the production of harmful proteins in ALS, cerebellar ataxias and dementias such as Alzheimer disease and FTLD. They are using ASOs that are chemically modified to improve uptake into nerve cells with overall reduced toxicity.
On the clinical translational end, Dr. Paolo Moretti and Meghan Zorn are using ASOs to treat patients with Huntington disease, a neurodegenerative disease of the brain leading to cognitive dysfunction and movement disorders. The ASOs are injected via lumbar puncture in collaboration with Drs. Christina Bokat and Scott Junkins from the Dept. of Anesthesiology. Patients are followed every month as part of a phase 3 clinical trial.Some ASOs have already received approval by the FDA. Russell Butterfield, MD, uses nusinersen, a splice switching ASO, to treat children with spinal muscular atrophy. Clinicians in the Department of Neurology played an important part in the early testing of nusinersen in the last decade.