Neuroscience, Rare/Orphan
Gene- and Allele-Specific Therapies for Development Epileptic Encephalopathies
2023 Harrington Scholar-Innovator
The diagnosis of developmental epileptic encephalopathies (DEEs) can be heartbreaking for new parents. DEEs are frequently associated with infantile-onset, drug-resistant seizures and severe cognitive and other neurodevelopmental impacts.
Children with certain types of DEEs have negative chromosomal mutations, or alleles, in a critical central nervous system channel that is responsible for modulating neuronal excitability. RNase H-activating antisense oligonucleotides—short snippets of RNA that can be designed to change levels of gene expression—can be used to induce selective, allele-specific reduction of mutant mRNAs. This reduces the amount of the mutant allele and improves the function of the remaining (non-mutated) allele.
With support from Harrington Discovery Institute, Dr. Yu and his team are seeking to develop a portfolio of drugs that could be used to treat children with DEEs. The challenge, Dr. Yu noted, is to safely “knock down” the bad copy of a gene while leaving the good copy of the gene intact.
A portfolio is required because targeting the mutated gene copy depends on the presence of certain genetic markers. As different patients may have different markers, any two patients with DEEs might require different drugs.
“Our goal is to develop these drugs, and then to launch the first clinical trials for kids with DEEs who require this allele- specific approach,” Dr. Yu said. “It’s a very challenging task. This concept has been around for many years, but yet to make it into clinical practice for this patient population. We are hoping to change that.”