Oligonucleotides that target Kv4.2 miRNAs for the upregulation of Kv4.2 protein in neurological disorders.
- Increases the abundance of the neuro-protective protein, Kv4.2.
- Offers a potential treatment for neurological diseases, including Fragile X syndrome, autism spectrum disorders, epilepsy, and Alzheimer's disease.
Nearly 50 million people are living with neurological disorders in the US. These disorders include Fragile X Syndrome, autism spectrum disorders, epilepsy, and Alzheimer’s disease, which combined affect nearly 9 million Americans. Currently, the vast majority of available pharmacological treatments for these disorders rely on symptom management rather targeted disease therapies. There are currently no miRNA-based drugs on the market; however there are over 20 miRNA clinical trials progressing for ocular and retinal disorders, cancer, kidney disease, and antiviral therapies; unfortunately none of the potential therapeutics are in trials for neurological disorders.
Neuronal excitability is tightly regulated, and defects in mechanisms involved in this regulation can lead to neurological disorders. A key player in the control of neuronal excitability in the brain is the A-type potassium channel Kv4.2. This potassium channel controls excitatory currents in the hippocampus and is thus critical to maintain a healthy excitatory balance in the brain. Emerging data suggests that Kv4.2 protein levels are dysregulated in a variety of disease states. Emory researchers have identified a microRNA that reduces Kv4.2 protein levels. An antagonist oligonucleotide, or antagomir, against this microRNA increases Kv4.2 protein levels in cultured neurons and induces an increase in cell survival after excitotoxicity-inducing treatments.
- Antagomir can successfully rescue Kv4.2 protein levels and increase cell survival after excitotoxicity-inducing treatments in vitro.
- Proof of principal experiments in mouse models of neurological disease have been initiated.