Allele specific knockdown of Cyfip2 R87C for treatment of early infantile epileptic encephalopathy (eiee/dee 65)
While there are no approved drugs for Cyfip2 associated Early Infantile Epileptic Encephalopathy (EIEE), studies in mice have shown one potential pathway to a treatment. Research in the laboratory of Dr. Kihoon Han at Korea University showed that mice expressing one healthy copy of Cyfip2 are less seizure prone than mice with one healthy copy and one copy bearing the mutation arginine 87 to cysteine (R87C). Mice lacking both copies do not survive long after birth.
Therefore, an antisense oligonucleotide (ASO) that only targets the R87C allele (the most common pathogenic variant) and not the wild type allele, would be expected to reduce symptoms in patients.
Allele specific knockdown is a specific type of RNA interference that targets only the pathogenic variant of the RNA using an RNA/DNA hybrid oligonucleotide called a gapmer-ASO.
This is a tricky balance to achieve, because efficiency in ASO function is due to a lot of factors besides the number of base matches in the sequence.
The allele specific knockdown will be tried first in cells from patients. This test is currently taking place at a laboratory at Washington University in St Louis.
If that’s successful, the ASO will be tested in mice to see if:
1) the ASO can reach the right kind of cells in the brain to affect Cyfip2 protein production;
2) are the symptoms in the mice reversed when they are treated after seizures are already seen;
and 3) is the ASO targeting the mutant allele safe?
The mouse model is currently being developed alongside this ASO pilot study. All updates will be available through the CYFIP2 Network as they become available. To learn more about how you can get involved in these research efforts, contact us at support@cyfip2network.org!