Excerpt

Two boys (aged 9 and 14) with severe developmental and epileptic encephalopathy caused by SCN2A variants (SCN2A-DEE) showed meaningful improvements in seizure reduction and neurodevelopmental outcomes after being treated with personalized antisense oligonucleotides (ASOs).

What It’s About

This study followed two individuals with two different SCN2A variants:

• One caused the production of sodium channels that were overactive (gain-of-function)
•  The other caused channels that were overactive at times but underactive at others (mixed function)

Each person was treated with an ASO built specifically for their own genetic makeup, but both ASOs were designed to reduce expression of the variant copy of SCN2A, while leaving the healthy copy alone (allele-selective).

Researchers tracked seizures and neurodevelopment in both boys over the course of two years while they were administered the ASOs, and both showed meaningful improvements with no serious adverse events:

• One was able to wean off a long-term antiseizure medicine that was causing adverse side effects, and also showed gains in communication, motor skills, and behavior
• The other showed a significant reduction in seizures, along with improvements in communication, motor ability, and gastrointestinal function

Even though each ASO was built for one specific person, it held the potential to help others with a similar genetic profile. To test that, researchers checked the genetic sequences of 19 additional individuals with SCN2A variants and found that 3 were close enough matches to potentially benefit from one of the ASOs in this study. It’s an encouraging sign that even a highly personalized drug could eventually help more than just one person.

Why It Matters 

This study adds to a small but growing body of evidence that ASOs can meaningfully help individuals with genetic epilepsies. Even though this particular study focused on SCN2A, it’s a hopeful glimpse into where personalized genetic therapy research is headed. 

This study was completed in collaboration with the n-Lorem Foundation, which is also working with members of the KCNQ2 community. Learn more about their ASO development process in our previous blog post and hear how this relates to our community in our recent webinar.

Quick Term

Allele-selective antisense oligonucleotide (ASO): A small, synthetic piece of RNA that binds to the RNA transcript from just one gene copy (you typically have two). Being allele-selective allows the ASO to target either the variant copy or the healthy copy specifically. Depending on how it’s designed, an ASO can either reduce how much protein gets made from the targeted copy (as in this study) or, in other cases, help boost production of a needed protein.

Link

Read Article