DBGen interviews Dr. Lorena Castillo, on International Leber Hereditary Optic Neuropathy (LHON) Day

Dr. Lorena Castillo is an experienced ophthalmologist and an international reference in optic neuritis and uncontrolled eye movement.

After graduating from the University of Zaragoza, she completed her residency at the Hospital Universitario de Bellvitge (Barcelona), nad had stays at the most renowned clinical centers in the United Kingdom in ophthalmology: Moorfields Eye Hospital, National Hospital for Neurology & Neurosurgery and St. Thomas’ Hospital. Currently, Dr. Castillo is Head of the Department of Neuroophthalmology at the Catalan Retina Institute (ICR). She reconciles this responsibility with her teaching work as Head of the Teaching Department at the ICR. She is also a  committee member of the Leber Optic Nerve Atrophy Association (ASANOL). She is a member of several scientific associations and has received the following recognitions for her research and teaching work:


  • Abstract of Distinction:  Evaluation of rAAV2/s-ND4 Gene Therapy Efficacy in Leber Hereditary Optic Neuropathy Using an External Control Group of Untreated Patients. Newman et al. American Academy of Neurology (AAN). 2021.
  • ICR 2º Prize for work on research into Ophthalmology: Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy. Catarino et al. J Neuroophthalmol. 2020 Dec;40(4):558-565.
  • ICR 2º Prize for work on research into Ophthalmology:  Leber Hereditary Optic Neuropathy: What are the therapeutic perspectives?. L. Castillo & J. Arruga. 2016 Dec;91(12):559-560.
  • ICR 1º Prize for best publication or submission of work on research into Ophthalmology: Estudio de la evolución de la NOIA-NA mediante OCT. Lorena Castillo et al. 2008.
  • 1º Prize: Valoració de 360º o feedback múltiple com instrument per avaluar el resident en la relació metge-pacient”. Salas et al. Jornada XCDC10 XII Jornada de la Xarxa de Comissions de Docència de Catalunya. 2010.
  • 2º Prize: Prioritats de formació percebudes pels residents en competències transversals. Parra et al. Jornada XCDC10 XII Jornada de la Xarxa de Comissions de Docència de Catalunya. 2010.


She has participated in multiple specialized conferences and has published the results of her research in books and scientific journals. We highlight her latest publication on relevant biomarkers for the diagnosis of LHON: Quantitative assessment of macular and circumpapillary retinal vessel density across all stages of Leber hereditary optic neuropathy using swept source optical coherence tomography angiography. Castillo L. et al. Acta Ophthalmol. 2022. (online ahead of print).



Today is European Leber Optic Neuropathy (LHON) Day. LHON disease is caused by mutations in mitochondrial DNA. What implications does it have in the inheritance, appearance and progression of this disease?

The fact that the mutated gene is located in the mitochondrial DNA implies that the inheritance pattern is exclusively maternal, since the sperm’s mitochondria does not end up forming part of the zygote. This means that males cannot pass the mutation on to their biological offspring, while all female carriers will pass it on. Regarding the appearance and progression of the disease, a mutation in mitochondrial DNA probably is not the only cause of the disease. LHON could in fact be a complex multifactorial disease.


Your professional career demonstrates a long and intense dedication to the study and diagnosis of LHON. Could you tell us what it was that attracted you to this pathology?

In the first place, I was struck by the number of unknowns pending to be solved about this disease. In many aspects, it defies logic, which, to me, makes its study intellectually very stimulating. Indeed, I do not quite accept not being able to grasp the full knowledge of the disease. Secondly, and more important, in my first years as a newly graduated ophthalmologist, when patients  were entirely my sole responsibility,  I was especially shocked to come across these cases. Among the first ones there were very young healthy boys, who suddenly began to lose their vision and within a few months, went blind. Apart from the diagnosis, at that time there was no approved treatment for this disease, I found that I could not do much more to help them than send them to ONCE. That broke my heart and I could not believe there was nothing else to do.


What are the main clinical features of LHON? Are there other symptoms related to LHON besides visual impairment?

In the vast majority of cases, the patient notices a more or less sudden, painless visual loss, in the form of a  spot in the center of vision, which prevents them from reading or recognizing faces. This worsens and follows a similar course in the other eye within a few weeks or months. Within a few months range, both eyes worsen and the patient ends with devastating visual loss, below the threshold of what is considered legal blindness. As a general rule, there are usually no other associated symptoms. In some cases, changes in the electrocardiogram can be detected and, in a minority of cases, other neurological symptoms can be associated, but usually the only manifestation of the disease is vision loss.


What difficulties does the diagnosis of LHON present? What is the impact of genetic diagnosis?

The main challenge that the diagnosis presents is the lack of suspicion. Although, fortunately, there has been an increase in awareness of this disease among ophthalmologists and neurologists in recent years, there is still a lot to be done to improve knowledge among professionals, since it is extremely difficult to diagnose a disease that is not suspected. The fact that there are no pathognomonic signs or symptoms of the disease makes the diagnosis complex and a thorough neuro-ophthalmological examination must be carried out. Genetic diagnosis is a KEY STEP, since it is required to confirm and put a name to this disease.


A high percentage of people carrying LHON-causing mutations does no develop any sympton. What is the reason for these differences between patients?

Indeed, only 50% of men and 10% of women carrying one of these mutations will end up with vision loss. We can gather from this fact that other factors must be involved in the development of the disease. We know that other genes in mitochondrial  and nuclear DNA can exert a modifying effect, increasing or decreasing the probability of visual loss, although a lot remains unknown in this regard. Environmental factors also play a role. As a matter of fact, tobacco and alcohol in large quantites are known risk factors. Estrogens have been shown to have a protective role. Some drugs can have toxic effects on mitochondrial function. Less well known is the role of diet, inflammation and stress, although they are also thought to be involved.


How do you value the efficacy of Idebenona in the treatment of this pathology?

Although it is not curative (unfortunately, no treatment developed to date is), it has shown a trend towards better final visual acuity, at least in a subgroup of patients, compared to the natural history of the disease. Changes that may seem small to people with good vision can have enormous implications in the lives of people with very low vision, since it can mean that there are a series of important tasks for them that they can start to carry out without help. Therefore, although we would like the efficacy to be greater, and as it is the only weapon that we currently have as a commercial treatment, I believe that it is essential that candidate patients have access to this drug.


How would you summarize the therapeutic advances for LHON? As it is a mitochondrial disease, are there any added difficulties in the design of gene therapies?

We are facing a paradigm shift in the field of genetic eye diseases.  Great advances have been made in recent years and gene therapy is already a reality for some entities and it is «knocking on the door» for others. On the other hand, these therapies are complex and their manufacturing is highly expensive. In the case of LHON, we find the added difficulty that the mutated gene is located inside the mitochondria.

Therefore the target gene has not an easy access because it is surrounded by a double membrane, the innermost of which is tremendously impermeable to charged molecules (and nucleic acids have many charges). For this reason, it has not yet been possible to introduce a gene inside the mitochondria with gene therapy techniques. What has been achieved, however, is what we call “allotopic rescue”. This consists of introducing the healthy gene (our passenger) together with a mitochondrial signal sequence into a viral vector (our vehicle). The product formed is injected into the vitreous cavity of the eyeball and travels to the nucleus of the retinal ganglion cells, where it is transcribed into messenger RNA. The signal sequence directs this messenger RNA towards ribosomes on the surface of the mitochondria, where the healthy protein is synthesized, and serves, at the same time, as a shuttle, to introduce this healthy protein into the mitochondria, in the place where it must perform its function. To date, all the assays that have been permorfed in human subjects have been limited to mutation m.11778G>A, the one with more prevalence and worst outcome. Preclinical studies for the mutation with the second worst outcome, m.3460G>A, are now starting to appear.


How do you envision the future of therapies and treatment for LHON?

I believe, as I have said before, that we are facing a paradigm shift in the treatment of genetic diseases of vision. For now, we have a very good start for LHON with a drug that we hope will be approved by the European Medicines Agency in the last quarter of 2023 for the  11778G>A mutation.

It should be noted that we do not expect this drug to be curative. On the one hand, it does not replace one gene (the mutated one) with another (the healthy one), but it makes copies of the healthy gene coexisting with copies of the mutated gene in different parts of the cell and, therefore, healthy protein molecules also coexist with pathological ones. On the other hand, it will not be possible to administer it to asymptomatic carriers, which would be when, ideally, we should act, before the cascade of events that leads to the catastrophic loss of retinal ganglion cells is set in motion and that, inevitably, continues to worsen vision to a point we call the «nadir.» Taking these facts into account, what has been shown is a significant visual improvement in approximately 75% of cases once vision has reached nadir state, which is far from what is expected by the natural history of the disease.

Probably, the development of new models of the disease based on retinal ganglion cells derived from induced pluripotent stem cells or  cellular organoids will lead us to a better understanding of the pathophysiological mechanisms of the disease and to the development of drugs that may be curative or, better still, that can be administered to asymptomatic carriers as a preventive measure against visual loss.


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