The road to treatment 15
Professor Marcela Votruba of Cardiff University in the United Kingdom, a researcher who discovered the link between ADOA and the damaged OPA1 gene, has spent years researching ADOA. Her research focuses on understanding the disease mechanism of autosomal dominant optic atrophy and designing therapies.
She researches new treatments, including drugs to protect mitochondria, gene therapies and light therapy. Idebenone is an option, but more research is needed. Genetic testing is important to find the right treatment.
ADOA patients should visit an ophthalmologist regularly and consider genetic testing. Patient organizations can provide valuable support and increase awareness.
It is crucial to make ophthalmologists, orthoptists and optometrists aware of ADOA to enable faster diagnosis. Patients' perspectives are valuable in understanding the disease and new treatments.
We interviewed Professor Marcela Votruba, one of the researchers who found the link between ADOA and the damaged OPA1 gene. She has been researching ADOA for years. A while ago we asked her to give a bird's-eye view of the research into ADOA.
Can you tell us in layman's terms what your research is about?
My research focuses on understanding the basic genetic cause of autosomal dominant optic atrophy, seeking to understand how the disease arises from the mutation in the OPA1 gene, and using this information to design both established and novel therapies and to test.
My research has been going on for several years and initially focused on identifying the OPA1 gene in the year 2000, and understanding its so-called phenotype - the clinical problems faced by ADOA patients. I then spent several years working in the laboratory designing different ways to model the disease. I have conducted research into the effect of the mutation in the OPA1 gene on the retinal ganglion cells in the eye, both in culture cells and in animal experiments with an artificial OPA1 gene mutation. The retinal ganglion cells are the cells most affected by the mutation in the OPA1 gene, and as a result, patients experience loss of central and peripheral vision, visual field, accurate vision and changes in color vision and so on.
Recently, the research and my laboratory have involved postgraduate students, master's students, PhD students and young researchers, as well as other clinicians. In the laboratory we have been able to test a number of new molecules that could potentially be beneficial as therapies, and we are also working to understand whether therapy is possible using a range of new approaches.
Is the main purpose of your research to find general answers to the topic of your research or are you also focusing on treatment?
The main goal of my research is currently increasingly focused on finding a treatment or even a cure. Although we don't yet know everything about how the disease develops in the cells of the retina, we already know quite a bit, and this allows us to test new treatments. It is a very exciting time in this area of research, as there are opportunities for therapies or new treatments arising from both gene and cell therapies, as well as drugs or new treatments that can be taken by patients by mouth or other means.
If you are looking for a cure, what stage are you in now and how long would it be before a therapy or cure for ADOA is actually available?
We are seeking a cure and are working with colleagues both nationally and internationally to achieve this goal. It takes many years to develop a treatment, from the time it is first proposed, tested in the laboratory, moved from cells to animal tests and then perhaps to other tests. Ultimately, initial clinical trials should focus on both safety, tolerability and the overall long-term safety of such a treatment. It is generally said that it takes 15 years from the very first idea to approval of a treatment. This is a long time, but we are already somewhat in this cycle and we hope that within the next five years treatments can be tested in patients, at least in clinical trials. After that, I am very optimistic, but we must also be realistic, because there can be setbacks and these processes take both time and money.
Do you expect to be able to stop or even improve the deterioration of ADOA patients if your research provides many answers about the degeneration process?
If we and others find treatments, including for example gene therapies or drug therapies, the most likely outcome is that patients will achieve stabilization of their vision and hopefully prevent further visual decline. However, it has been noted that when new treatment is initiated, as long as the patient is not in a very advanced stage of the disease with extremely poor vision and significant loss of the retinal ganglion cells, there may sometimes even be a slight improvement in vision once the treatment has started. However, this is not always the case and it is not easy to explain how this could happen in the majority. This would require the retina to grow new retinal ganglion cells, which seems quite unlikely at this point.
Do you have any idea what a treatment might look like?
New treatments for ADOA may include new drugs designed to protect mitochondria. These could be small molecules, antioxidants, neuroprotectants or a combination of mitochondrial support and the like. Other new treatments could clearly be gene therapies, so-called gene therapies, or therapies that introduce some form of genetic intervention into the eye to increase production of the normal OPA1 protein needed for the healthy retinal ganglion cells to survive and function . There are real opportunities for these treatments at ADOA, but there are still many obstacles to overcome. It is difficult to speculate whether any form of stem cell or cell therapy could be effective in ADOA, but I would be very excited to see this field expand and more research be done.
In a video several years ago you mentioned Idebenone as something that might help. What is your opinion on Idebenone right now? Do you recommend ADOA patients to use it?
Idebenone is a drug approved by the European Medicines Agency for patients with the disease Leber's hereditary optic neuropathy (LHON). This is not a drug approved for use in ADOA. However, there are researchers treating individual patients and small case series of ADOA patients with the drug Idebenone. These studies have been published and are being discussed in the scientific community. There is an indication of some possible benefit, but it would really require a proper double-blind, placebo-controlled, randomized trial in which patients receive the drug Idebenone in one group and a so-called placebo in the other group. It also requires that patients be followed for several years before we can say whether the outcome has indeed been favorable.
At this time I cannot use Idebenone in ADOA patients in the UK as it is not approved or licensed for this disease, and at this time we are not using Idebenone in individual patients until there is more evidence.
You recently wrote a review and mentioned red light therapy. You've actually summarized a whole range of potential treatment approaches. Our question is: which approach do you consider most promising? Because there are many!
Thank you for asking about our work with so-called near-infrared or red light therapy, which is sometimes called photobiomodulation. This is the use of light to send specific wavelengths of energy to cells, which under certain conditions can potentially alter the expression of certain genes and proteins that may play a role in either healing, cell survival, metabolic processes, or other cellular processes that are essential for the function of cells. Research has been done with so-called near-infrared light or far red light in wound healing and other conditions, but it is still questionable whether it really has a beneficial effect. We have used two wavelengths of light in some studies in the laboratory, exposing cells and retinas of mice to the light for different periods of time. We investigated whether the retinal ganglion cells are able to show any improvement in their energy metabolism or other factors such as the production of reactive oxygen species and thus live longer. There is some interest in this area as there are some positive results, and it is really important that we continue this research to show if this is a real effect and if so is it safe and will it have a long term effect .
We understand that you also see patients and we also have some questions about this. Do you have any advice for patients with ADOA or ADOA plus?
I am a clinical scientist, which means I am an ophthalmologist trained in ophthalmogenetic disorders of the retina and optic nerve, and I see ADOA patients in my clinics. Over the years I have seen many patients and families, and my PhD research many years ago brought me into contact with this disease and with the individuals who have it in the UK. If you want me to give general advice, I would definitely say that patients with ADOA or ADOA Plus should ensure they are seen locally in an ophthalmology clinic, on a regular basis, even if this is only once a year. This will allow monitoring and collection of good information about the status of their retina and optic nerve. This includes taking pictures, retinal exams, imaging, visual field tests, color vision tests and the like. I would also recommend doing a genetic test. At this point patients may feel like this is of little use to them, but I really want to emphasize how important it is for all patients with ADOA or ADOA Plus to be under control, as they can also be supported with visual rehabilitation, assistive devices for the visually impaired, networking with social services and other matters. What is most exciting, however, is that if there are indeed new treatments to be evaluated in ADOA patients in the future, it will be extremely valuable to have information about their condition going back several years.
What is your perspective on genetic testing?
As an ophthalmologist, I regularly discuss testing the patient's DNA in so-called genetic tests to understand which gene is affected and therefore the underlying genetic cause of their disease. My perspective on genetic testing is that it is now extremely important that patients receive a genetic or molecular diagnosis of their underlying condition. The reason for this is that we need to be able to demonstrate which gene is affected and therefore which potential new treatment could be applicable for that patient. Genetic testing should be performed with the full knowledge that we will be screening for a number of genes known to be causes of optic atrophy, and that the OPA1 gene, which is the leading cause of ADOA, is one of them. Overall, we hope that we can feedback the result to the patient in a reasonable time so that they can gain a better understanding of their own condition and why they are affected. However, it is important to ensure that both the patient and their family understand the implications of having a genetic test and that they are given sufficient information and time to understand this and make a decision about having it carried out test. The test is performed on a small sample of blood or even buccal mucosa and saliva. We take what's called informed consent. Genetic testing can also help other family members who may be mildly affected to understand whether they are carriers of the same condition. Genetic testing has become increasingly available and in recent years most patients with hereditary eye diseases are receiving their molecular diagnosis. I believe this change in our knowledge is incredibly important and is also one of the biggest drivers for the development of new treatments, as we realize how many patients are affected by genetic eye diseases.
Can you share your thoughts on why it is important for patients to get organized?
ADOA is what is called a rare disease, but that doesn't mean it doesn't affect thousands of patients around the world or even across Europe. Patients with rare diseases often struggle to get the best and most up-to-date information about their condition at their local hospitals and may need to be referred to more regional or national centres. However, the existence of a patient organization can be very helpful in providing support and information for both known and new ADOA patients. I think it's very important for patients to get organized. It is also important to think about the future, when we hope there will be new treatments. To generate publicity and reach ADOA patients, patient organizations can potentially be very useful and useful become important.
What information should we as Cure ADOA Foundation share with ophthalmologists, orthoptists and optometrists to help them recognize ADOA or ADOA plus? We want to help shorten the time it takes for the correct diagnosis.
You are absolutely right when you say that one of the biggest problems for ADOA patients is to get the best and correct diagnosis as quickly as possible. I have spoken with many ADOA patients, and this has been one of their major concerns. It must be extremely worrying and stressful to be in the position of not having full knowledge of the cause of your own or your child's vision problems. That is why both ophthalmologists and genetic tests are really crucial in this process. The Cure ADOA Foundation plays an extremely important role in publicizing the condition, both to provide support to patients and to signal that the individuals affected by this disease want to know more and indeed be involved in both its development and the application of new treatments. I think ADOA patients can offer unique insight into their own condition, which is of course completely invaluable for understanding the impact of the disease and therefore the potential impact of new treatments. The effect of ADOA on both quality of life and other health outcomes and markers should be significant, and it is extremely important that ophthalmologists, orthoptists and optometrists understand and recognize what the patient is going through. I know it will become increasingly important that patients are involved in discussions about new treatments and their opinions will also be hugely important in determining what makes sense for them in terms of a treatment. Please continue what you are doing, and I think it can only become more powerful and meaningful as we begin the process of new treatments in the future.
