The same person familiar with the Stoke Therapeutics research has contacted a research team from Italy and Greece this time. This in response to the article below and with the goal of getting a simpler explanation of what they do and an estimate of what the expectations are for the future. There is research being done by these researchers on ADOA for 18 years!!!

The research is called Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy. And through either of these links you can read it in full: https://www.nature.com/articles/s41467-020-17821-1 or https://rdcu.be/b840e

With the answers to our mails to the researchers and by means of having the medical paper read carefully by an acquaintance who is knowledgeable about such studies, we have come to the following report;

ADOA is caused by a defect in the OPA1 gene. This causes mitochondria (energy factories of our cells) to malfunction. Because they are not working properly, self-destruction mode (autophagy) is turned on and they die. In addition to providing energy, mitochondria are also important in the optic nerve to relay signals from the eye to the brain. So if there are not enough of them, those signals cannot be passed on.

The researchers have shown in mutant cells that this self-destruction mode is a big problem and if they turn it off, there are as many mitochondria in the nerve cells as in healthy cells. They’ve also done this in mice. They made a mouse model where some of the optic nerve cells don’t have an OPA1 gene. As a result, the mice lose much of their vision when they reach 4 months of age. If they then turn off part of that self-destruct gene as well they see that the mice just keep their sight when they are 4 months old. They keep their sight until at least 12 months (they haven’t looked any longer). What is important though is that they have already turned off the self-destruction mode from birth. They don’t cure the mutation, nor do they restore sight.

The way they used in the paper at this time is not applicable to humans. In the interview they talk about drugs/substances that they want to start testing to see if that has the same effect. That is especially very interesting because they might be able to use that for humans. Furthermore, they also said that they don’t expect vision to get better again but that it won’t get worse. So not cure but delay/stop.

Because you have to take the medicine for the rest of your life you could use a pump under the skin. This is just an idea and unfortunately they are still far from that.

Nor can the researchers predict when there might be a therapy. They think they will need five years to test the drugs. Suppose something works super well then a clinical trial could be organized. But this also takes a number of years depending on a lot of factors. So this is also really unpredictable.

The researchers also indicated that this approach will probably and unfortunately not work for ADOA+ since other processes play a role here.

We will continue to monitor this research!

An acquaintance of ours decided to approach Stoke Therapeutics, a pharmaceutical company which recently published a study on a possible treatment for ADOA. Someone was willing to talk to him and answered a few questions! Please note that all answers are the interpretation of the interviewer and not necessarily that of Stoke Therapeutics.

As a public company, why are you guys focusing on ADOA?
The treatment of ADOA as they envision it closely parallels a study they are doing to remedy certain epilepsy variants (Dravet syndrome). In addition, there are a number of conditions that can be approached in the same way, although the final drug will be different. All in all, they think they can address several conditions with this technique.

Is ADOA-plus also included in the research?
No unfortunately ADOA-plus is not included. The underlying cause in ADOA-plus is just a bit more complicated than in ADOA and therefore it will not work. I will come back to this in the next question. 

What does this research entail?  (explained as simply as possible)
Everyone consists of 50% DNA from their father and 50% DNA from their mother. Everyone has two OPA1 genes. The OPA1 gene ensures that a protein is produced that ensures proper functioning of the mitochondria. In people with ADOA one of the OPA1 genes, which can originate from either the mother or the father, has an error, or rather a mutation. Sometimes such a mutation occurs out of the blue, without the parents passing on a mutated gene. Stoke Therapeutics thinks it has the solution to this process by stimulating the healthy OPA1 gene to make more proteins to compensate for the mutated OPA1 gene. In ADOA-plus, there may be more going wrong than just 1 mutation in the OPA1 gene, but exactly how is not yet fully understood. Because sufficient stimulation is required and there may be more going on in ADOA-plus, the idea is that this does not work in this patient group. He also mentioned something along the lines that in that case you run the risk of stimulating other substances with the result that things get worse.

Which phases does the research consist of?
The research consists of a number of phases. The current research consists of testing on rabbits. Here they have successfully demonstrated that more proteins are produced by the healthy gene after their treatment. Whether this also has the desired effect on stabilization or improvement of vision they cannot measure with rabbits. They expect to start the next phase next year. In this phase they will research the risks and/or side effects that the treatment may entail. This phase is expected to take 1 to 1.5 years. Then they can start testing on humans.  This last phase is split into three. First they test on a small group of adults, then on children under 18, and then on a large patient group. Each subphase normally takes 1.5 to 2 years. Stoke Therapeutics can look

In a nutshell, the phases (as of now) look like the following;

• Testing on animals (as good as completed)
• Toxicology studies (start in 2021), duration 1 to 1.5 years
• Adults, duration 1.5 to 2 years
• Children, duration 1.5 to 2 years
• Large study group of patients, duration 1.5 to 2 years

Do you expect stabilization or improvement of vision after treatment?
In principle, it is expected that stabilization of vision will be achieved. However, there are also weak cells that may start functioning better again, which may also lead to a small improvement, but they cannot make any serious statements about this yet. 

What will a possible treatment look like?
Each patient will receive an injection directly into his eye once or twice a year. This will be done with a very thin hypodermic needle. This will have to continue for life.

In summary, this research is still in its infancy, but the initial results are favorable. However, they are in the early stages of their research on OPA1 and as a company they have not yet decided to continue with this research. This depends on the ongoing studies. In any case, we are very curious about the future of this therapy and hope that it can be a godsend for a large portion of our fellow sufferers. Unfortunately, they think in advance that this is not going to be a solution for people with ADOA-plus, but it is possible that there is another solution on the way for these patients. It is nice to know that research is being done and that we are not being forgotten.