Current state of affairs: Stopping the disease versus truly curing
In a recent review article in the scientific journal Expert Opinion on Therapeutic Targets, Dr. Marcel V. Alavi (2026) describes that there is currently a clear and hopeful movement underway in the pharmaceutical industry. The focus here is now primarily on stopping or inhibiting the disease. The most advanced programs currently being tested in humans for safety and tolerance are antisense oligonucleotides (such as the molecules PYC-001 and STK-002). These are advanced RNA therapies, or RNA patches. These treatments are administered via an eye injection and are designed to directly replenish the deficiency of the functional OPA1 protein in the cells.
Although these developments are very hopeful for halting further decline, real healing – in the sense of restoring vision that has already been lost – is unfortunately still further away. While researchers are indeed looking at reconstructive medicine (such as transplanting new stem cells to repopulate the affected cell layers), this encounters enormous biological barriers. The newly placed cells must grow nerve pathways all the way to the brain and make connections at the right place there. In an adult, already damaged environment, this is extremely complex. The emphasis of the medicines that are now within reach therefore really lies on preserving what is there.
Limited options for ADOA-plus
After 25 years of gene discovery, the research finds itself at a major tipping point and junction. Two distinct pathways are identified that hold great potential for the future:
1. Promising for ADOA (focused on the eye): The genetic approaches that directly target the OPA1 gene are the most concrete. In addition to the antisense therapies already in clinical trials, laboratory techniques such as CRISPR activation are also showing good results in experimental models. This acts as a kind of biological 'volume knob'. It is a technique that turns up the cell's own, still healthy, OPA1 protein production to a much higher level. Specifically, the goal of CRISPR activation is to stimulate the cell's own healthy protein production, and specific modifications for genetic 'splicing' defects (such as U1 snRNA) are showing good results in experimental models. Splicing is the 'cut-and-paste' of genetic blueprints in our cells. If there are errors in these, the cell cannot produce a proper protein. The molecule U1 snRNA acts as precision scissors to repair this cut-and-paste work. Important insight: Scans show that the deterioration of the nerve layer in ADOA likely already occurs partially during early development in the womb. This means that in the future, genetic treatments will presumably have the highest effectiveness if they are started as early as possible in life (for example, as early as early childhood).
2. Promising for both ADOA and ADOA-plus (body-wide): A very promising pathway that could also offer a solution for ADOA-plus patients focuses on alternative proteins in the cell: OMA1 en DNM1L. Under normal circumstances, these proteins regulate the stress responses and cell division of our mitochondria (the cell's energy factories). However, in the case of an OPA1 deficiency, these proteins cause mitochondria to fragment and cells to die more rapidly. Blocking OPA1 or DNM1L with medication (in the form of small molecules, such as traditional pills) offers a strong cell-protective strategy that bypasses the complex OPA1 correction. Laboratory studies have already demonstrated that a DNM1L inhibitor (Mdivi-1) can successfully correct mitochondrial abnormalities in cells from ADOA-plus patients. The major advantage of this type of medication is that it is developed as a small molecules. These are traditional medications (such as a pill) that are small enough to easily travel throughout the body via the bloodstream. This opens a promising avenue for addressing muscle and nerve complaints outside the eye in the future as well.
Ready to see how Snowflake works?
We are moving faster than ever towards targeted treatments. Although older agents from ophthalmology (such as idebenone/Raxone) show little effect in ADOA, the ongoing trials are opening with RNA therapies and the laboratory research into mitochondrial protectors New, promising avenues that hopefully offer prospects for stabilizing the disease in the future. The focus is therefore now on finding ways to preserve what remains, while a true cure — in the sense of restoring vision that has already been lost — lies even further in the future.
Author: Peter Makai
