Simon's ASO Therapy
What is an Antisense Oligonucleotide (ASO) Therapy?
ASOs are short, lab-made strands of genetic material built from the same building blocks as our own DNA and RNA. The easiest way to picture them is as a tiny, highly precise strip of tape that sticks to one — and only one — target inside a cell.
That target is messenger RNA (mRNA): the short-lived “recipe” a cell follows to make a protein. By binding to a chosen mRNA, an ASO can either stop a harmful protein from being made or correct the recipe so a missing protein works again.
This precision is what makes ASOs so promising for genetic conditions, including rare diseases Lauffer et al. 2024. Because ASOs work on mRNA rather than on DNA itself, their effect is temporary – patients need repeated doses to keep the therapy effective.
How does an ASO therapy work in patients with MCOPS12?
In most patients with MCOPS12, one copy of the RARB gene is mutated while the other copy stays healthy. Both copies produce mRNA, but only the mutant mRNA leads to the production of a harmful version of the RARB protein.
An ASO can be designed to recognize only the faulty mRNA. Once inside the cell, it pairs with that mRNA like two halves of a zipper (see figure below, panel 2). A natural enzyme called RNase H1 spots this pairing and destroys the faulty mRNA — so the harmful protein never gets made. Scientists call this “mRNA knockdown“.
The catch: the ASO has to be allele-specific — it must silence only the faulty copy and leave the healthy one untouched. That’s because the healthy RARB protein is essential for normal brain development. Knocking it out by mistake would cause the very symptoms we’re trying to prevent Ciancia et al. 2022 .
Simon's personalized allele-specific ASO Therapy
The development of an allele‑specific ASO therapy is inherently challenging Hauser at al. 2022.
Simon carries a RARB mutation called c.1159C>T (p.R387C), which is shared by about 30% of MCOPS12 patients. Unfortunately, computer modeling showed that targeting this exact mutation was not going to work.
So we took a different route. Using advanced genetic analyses called long-read sequencing, we mapped Simon’s faulty RARB copy (allele) in detail — and identified dozens of additional unique markers found only on the mutant allele. Each one is a potential bullseye for an allele-specific ASO.
This is exciting!
First, it opened a real path forward for Simon’s ASO therapy.
Second, the workflow established here (Figure below) is a blueprint – one that can be reused to develop personalized ASO therapies for other children with MCOPS12.
Target identification, ASO design and efficacy screening was performed at RareLabs (a division of AlphaRose Therapeutics)
Additional designs of ASOs and safety testing in Simon´s cell model was performed at a large pharma company (undisclosed).
ASO drugs for in vivo safety studies were produced at Hongene Biotech.