UC San Diego

Focal Malformations of Cortical Development (FMCD) are neurological developmental disorders that are a major cause of drug-resistant pediatric epilepsy. Along with seizures, patients display disrupted cortical architecture and neuronal organization. Current treatment involves invasive surgical resection of the epileptic focus, which may only show partial benefit. Recent studies have identified several categories of post-zygotic somatic mutations that cause FMCD, however this effort has not yet been utilized to generate therapies. Antisense oligonucleotides (ASOs) are safe, stable and programmable molecules that can be designed to target specific mutations such as those that cause FMCD. To demonstrate the therapeutic potential of ASOs against FMCD, we introduced AKT3E17K, an FMCD causing variant in mice brain and subsequently treated them with ASOs designed to silence the toxic gene. The ASO treatment was able to rescue cortical architecture. Later studies may explore the dependency of treatment on the stage of the disease, the dose of the drug, and the type of FMCD causing mutations. Successful development of ASO therapy can provide safe, effective and non-invasive treatment for FMCD.