In order to celebrate International Sight Day, DBGen wanted to bring attention to rare vision pathologies and to to highlight to people who persevere in the search for a genetic diagnosis as an essential requirement to access effective treatments.
We have brought together the presidents of some of the associations of patients affected by retinal dystrophies to tell us how they accessed genetic diagnosis and give us their view on future prospects for accessing possible treatments.
DBGen greatly appreciates the dedication of these associations in favor of the patient. Their contribution materializes by facilitating contact with patients and ophthalmologists to achieve a positive genetic diagnosis, which is sometimes difficult to obtain. In addition to promoting knowledge and research on hereditary pathologies of vision, they accompany patients in understanding and accepting the results and guide them regarding current and future therapeutic options.
Andrés Mayor chairs the ESRetina Asturias, and the Spain Vision Action Association (AVE), an entity that brings together 13 visual pathology associations in Spain. He is the acting leader of the Retina Iberoamérica project, giving an international dimension to its associative work. It has promoted research into pathologies of vision through projects and awards for scientific work from the different entities in which it participates. Andrés Mayor is a strong supporter of patient associations as promoters of the advancement of science and the search for treatments that cure and/or prevent blindness. It carries out a great work of outreach and support to affected people and their families through informative projects such as the Vision magazine and the website retinosis.org.
Marcela Ciccioli is president of Stargardt APNES Retina Argentina and a prominent member of the Pan American Group of Hereditary Retinal Dystrophies (PANIRD). She is a biologist and geneticist. She carries out intense work to inform and advise patients and families affected by hereditary pathologies of vision to facilitate genetic diagnosis and inform them about possible treatments. She is a tireless fighter to promote and facilitate genetic diagnosis. Its pioneering activity in Argentina to promote gene therapy for those affected by Leber’s hereditary optic neuropathy (LHON) should be highlighted.
Dr. Margaret Creus is a pediatrician and mother of a Stargardt patient. She is co-author of the «White Book of Inherited Retinal Dystrophies», a clinical guide addressed to ophthalmologists for the diagnosis and management of these pathologies. She is also responsible for the StargardtGO/ PedRetina project, focused on the dissemination of pediatric retinal dystrophies. It reports on biomedical advances and generates a little joy and optimism for those affected.
Miguel Ruiz is the founder, coordinator and president of the CRB1 Spain and Latin America Group, an association for patients with retinal diseases caused by mutations in the CRB1 gene. As president of the association, he guides patients and relatives about diagnostic possibilities, and informs them about the state of development of future therapies. It also collaborates with research groups and other associations of related pathologies.
How much time elapsed between the appearance of the first symptoms and reaching the genetic diagnosis?
A. Mayor: I recall seeing badly since I was a child, although I did not know what was happening to me. I was scared in dimly lit environments and I very clumsy in games and sports. At the age of 14, I discovered that I saw poorly in the dark compared to my campmates, and it was on my medical exam before the military service that an ophthalmologist diagnosed me with retinitis pigmentosa.
I took the first blood sample for genetic study in 1994 but without positive results. It was in 2018 when my gene finally was discovered, because until that year it was unknown. The hard work of Dr. Roser González’s group made it possible to establish that a novel gene was causing retinitis pigmentosa in my family.
M. Ciccioli: We had Victoria’s clinical diagnosis in 2001, but we did not reach her genetic diagnosis until 2012. In our case, it happened by chance, as the ophthalmologist who attended the family was a retina specialist and resolved the clinic quickly, but in most cases, the diagnostic odyssey for the patients takes 5-7 years, multiplying the anguish, , the unnecessary studies and themedical visits. in the absence of diagnosis, there is a risk of worsening the situation. For example in our case, supplementation with vitamin A and the use of filters that prevent blue (short wave) light from reaching the retina is not recommended to patients affected with Stargardt disease. Without accurate information, access to adequate management is prevented, even when therapies are not yet available.
M. Creus: My eldest son began to present symptoms of visual impairment at the age of 8 and we obtained the genetic diagnosis when he was 12 yo.
M. Ruiz: Well, I was one of the first patients to undergo the genetic test in Andalusia in 1995. Of course, without positive results because at that time my “variants” had not yet been annotated in databases. The results arrived in 2019, which showed that I was a carrier of 2 mutations in compound heterozygosity in the CRB1 gene.
Obtaining the genetic diagnosis, what did it mean for you and your family?
A. Mayor: It has been a great joy because it has eliminated many doubts about our descendants and has explained what is happening to us.
M.Ciccioli: For us, it was very important to corroborate the clinical diagnosis with the genetic diagnosis. We were relieved to know that there was no other underlying pathology, and it allowed us to make appropriate decisions regarding management for school and work inclusion.
M. Creus: Given that mutations in ABCA4 are associated with different pathologies, most of them with poorer visual prognosis than Stargardt disease, knowing our son genetic mutations was, in a certain way, recomforting. On the other hand, the distressing side was that our other children might be also affected. Discovering through genetic analysis that they were carriers of a single mutation and that this meant it would be very unlikely for them to develop the disease was really encouraging.
Besides, the great advances on gene therapy treatments bring great hope to as they could change their lives. Under this perspective it is clear that having genetic studies and diagnoses is essential.
M. Ruiz: Having a genetic diagnosis in a rare disease is fundamental, in my case it changed my life and I found the answers to many questions that before had no explanation. In terms of clinical and family benefits, they are also essential, one of the most important issues is knowing the inheritance pattern of the disease, to prevent transmission to offspring. In Spain, it is regulated by law, in the Royal Decree 259 of 2014. Another very important issue is learning about gene therapy options, to check if there are clinical trials or treatments available.
Moreover, I cannot forget that it was thanks to the genetic diagnosis, that the CRB1 Group Patient Association could be launched. We collaborate with other affected families, so that we can join forces in developing therapy for CRB1 and of course promote visibility to those affected by mutations in this gene. We aim to give them all the information and support possible, so that they can have a true and clear idea of the present and future of this disease.
Do you think that retinal diseases receive enough support from public institutions?
A. Mayor: Retinal dystrophies and vision pathologies in general are of little interest until a case appears in our circle.
Spain needs a large Vision Research Center that is capable of supporting and coordinating the work of the different groups that exist in the universities and research centers. A center that is capable of attracting all the people who are doing research outside of Spain due to the lack of opportunities in our country.
A national strategy for the prevention of avoidable blindness is needed, led by the government and agreed upon by the Interterritorial Health Councils, with specific plans for early diagnosis, both clinical and genetic, neonatal screening, visual rehabilitation, psychosocial support and support for families, all of it with well-funded budgets.
M. Ciccioli: They definitely do not receive adequate support. Genetic diagnosis in Argentina is mandatory when hereditary diseases are present, however we do not have public hospitals that deal with it, and the private health system continually denies orders. In the event that they deal with it, we have to resign ourselves to low-performance studies with a high percentage of negative inconclusive results, rendering them useless. Our association, through the Agreement with DBGen, has been able to resolve many cases, relieving the anguish of more than 700 families, and we hope to continue doing so in the future.
M. Creus: I don’t think they receive any support. It is difficult to understand. We are facing a paradigm shift in the medical world and for the first time we are faced with new scenarios to treat up to now untreatable diseases. The retina is an ideal organ for applying precision therapies. It seems obvious that any country that prides itself on being advanced should make the effort to advance in this direction. It is not the case of the Spanish state, we are very far from the advances that are being achieved in other countries.
If we also take into account that Spain is one of the longest-lived countries in the world, and this implies an increase in the number of people who will present age-related vision loss, not worrying about this issue implies serious irresponsibility from different administrations.
M. Ruiz: I believe that a patient with an Inherited Retinal Dystrophy (IRD) in Spain is well cared in most cases. We have to bear in mind that inherited retinal diseases are a heterogeneous group of monogenic diseases, for which there is only one approved treatment in Spain. I believe that, like everything in life, there is room for improvement. In this sense, improvements in care and early diagnosis should be established in specific clinical Reference Units where knowledge of these pathologies can be increased and also in Genetic Services in hospitals, so that genetists would work together with ophthalmologists, since Spain is the only country in Europe that lacks the specialty of Medical Genetics.
Considering the current advances in therapy, how do you imagine the near future for patients with retinal pathologies?
A. Mayor: The future is very promising. We already have a gene therapy that is restoring lost sight and I am sure that many other therapies will come that will allow many people not to lose their vision and that some others will even recover their vision.
The research is bearing fruits and I hope that Spain is not left behind, which is why it is so important that we all join forces so that the train of personalized therapies does not pass by.
The people affected and our families offer all our support to achieve this. We are part of the solution.
M.Ciccioli: We are very excited about the paradigm shift regarding therapies for hereditary retinal dystrophies. It took 20 years to reach the approval of the first gene therapy for the RPE65 gene in December 2017, and nowadays there are more than 50 clinical trials of different types underway and around 120 preclinical trials, to as many genes. We are excited that there are many scientists doing their best to make these trials safe and effective and that we may have the opportunity to treat our children in the not too distant future. We are willing to collaborate so that over time these pathologies can be resolved early.
M. Creus: I am optimistic in this sense. Thanks to new treatments, possibly the combination of gene therapy with regenerative medicine, many patients will be able to stop the deterioration of the retina or even restore its function. I am convinced that there will be people who will recover their vision and will have to undergo visual rehabilitation to learn to see again.
M. Ruiz: The future of patients with IRD today is very encouraging and optimistic. The main reason is the great progress in gene/cell therapies that has been taking place in recent years, with an approved therapy for the RPE65 gene, called LUXTURNA, and more than 20 ongoing clinical trials for other genes. We also have 4 clinical trials of cell therapy, gene therapy trials for the activation of inactive genes for retinal regeneration, such as that of the Endogena company, optogenetic therapies, artificial retina implants, etc… But we must be very sure that once ready the developments of advanced therapies are approved by drug regulatory agencies and the clinical trials comply with current legislation.
Today the tools for the development of these advanced therapies already exist and we only have 2 alternatives as a country, either research is promoted from public funds, or we will pay astronomical prices for these new therapies, which in the end will be much more expensive than the research.