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Interview with Marcela Ciccioli on progress of LHON patients treated with gene therapy in China

07/03/19 - Patients, Gene Therapy,

We firmly believe that the achievements of women in the field of hereditary eye diseases have to be made visible and acknowledged worldwide. For this reason, and to celebrate the International Women’s Day, we have interviewed Marcela Ciccioli, President of Stargardt APNES Retina Argentina.

Marcela is a tireless fighter, a source of energy and a beacon of hope. Her firm determination made it possible to engage 10 Leber Hereditary Optic Neuropathy (LHON) Argentine patients in phase 3 clinical trial of gene therapy, an assay carried out by the consortium of Tongji Hospital, Tongji Medical College and Huazhong University of Science and Technology, at Wuhan, Hubei region, People’s Republic of China. These are the first Latin American patients who have participated in a phase 3 gene therapy trial to treat an inherited eye disorder. Marcela tells us her experience, the news about the prognosis of these patients and her future projects.

Marcela Ciccioli, BSc in Biology from University of Buenos Aires, an expert in Genetics. President of Stargardt APNES Retina Argentina (Association of patients and parents of children with Stargardt disease).


What were the steps that Stargardt APNES had to follow to enroll 10 patients with Leber hereditary optic neuropathy (LHON) in this gene therapy clinical trial?

In our annual meeting at the end of 2017, we presented and shared the updates and news in the field of hereditary eye disorders. In this event, we communicated to ophthalmologists and researchers the advances in diagnosis and therapy and informed the patients of the treatment advances for each pathology. Among them, a phase 3 gene therapy clinical trial for LHON was presented. This assay was being carried out at the Huazhong University of Science and Technology and registered in a global database of clinical trials. Several boys in our association met the specific requisites for this therapy: between 15 and 22 years old and were carriers of the 11778 mutation in the mitochondrial ND4 gene. The fact that they had already been diagnosed at the genetic level was crucial to move forward. The trial looked promising and interesting; it was in clinical phase 3, meaning that biosafety had already been approved, overall supporting that it was the right time to find out the possibilities to include some of our patients in the trial.

Stargardt APNES Retina Argentina is a member of the Network of the Association of Patients for Advanced Therapies (Red APTA), established network within the Ministry of Science, Technology and Productive Innovation (MinCyT) of Argentina that works in coordination with the Advisory Commission on Cellular Therapy and Regeneration Medicine. The commission is formed by renowned scientists specialized in regenerative medicine, and cellular and genetic therapies for all types of pathologies. Our first task was to verify with them the scientific rigor and quality of all the publications reporting the data obtained in this clinical trial. And we could confirm that the research led by Professor Bin Li of Huazhong University of Science and Technology had complied with all the established regulations to complete phase 1 and phase 2, which involves giving a full report of the adverse effects detected in patients after the trial and of the clinical data supporting that the therapy, so far, had been successful.

Once we concluded that the therapy was promising and the affected children met the conditions, we addressed our query to the Advanced Therapies Commission of APTA. In addition, we told the families of the LHON patients, who were very anxious, that if the commission approved our request to apply for the trial, Stargardt APNES Retina Argentina would do everything in its power so that the patients were included in the trial. Finally, the commission agreed that the trial fully complied with the bioethical standards, the correction of the pathophysiological mechanism was clear and that it was practically free of charge for the participants. In this context, APTA approved the move to try to get acceptance of patients to the clinical trial.

The next step was arduous negotiations, which had to be very fast because the trial time slot for acceptance is very short. It took us several months of conversations with the researchers involved. It happens that LHON is a major retina hereditary disorder in China, the number of candidates for the therapy was very high and the official policy was that they had to be prioritized. The agreement came after long talks, and the Argentine patients could be included. I think the reason that made them change their minds was the fact that, by participating patients from a distant human population, it allowed them to broaden the scope of the trial because it was going to be tested on patients who did not have a Chinese origin.

The team leading the gene therapy assay finally accepted seven Argentinian patients; who after careful evaluating of their medical record traveled to China in May 2018. In the case of this particular trial, they told us that they were particularly interested in the state of the optic nerve and the onset of the pathology was not of relevance. This surprised us because we had tried to get the acceptance of LHON patients in similar gene therapy trial and were told that only those with less than a year of onset less could be accepted, which is quite difficult to achieve.

After this first trip, the researchers wanted to include patients with different times from the onset of the pathology, probably to evaluate how the optic nerve reacts to therapy with respect to different times from the beginning of the pathology. For this test, they chose patients from 3 months to many years from the age of onset. In a second stage, three Argentine patients traveled, an eight-year-old boy who had been with less than a year onset, and two young people of 31 and 34 years old, one with 10 years of pathology and the other with 14 years of pathology. In total, there were ten patients, in two groups, a group of seven patients in May and another of three patients in late November 2018.


What were the initial improvements and the visual progression to date of treated patients?

The results were very good. I want to emphasize that the researchers were very hospitable to the patients. The first seven patients traveled with a companion and the last three traveled only with the mother of the youngest child. In addition to the companions, the patients enjoyed great attention and careful care from the researchers, doctors, and nurses of the Tongji Hospital. None of the young Argentinians speaks Mandarin and a few of them have a good level of English. Since their arrival in China, a translator helped them to adapt to the new situation, but he was not there all the time. Consequently, the support and constant attention given by the researchers and hospital staff to the team was very relevant to make them feel well and this has greatly contributed to the benefits of the trial.

From the moment of injection, which is performed only in the most affected eye, some patients already manifested changes within a few hours. Some declared visual progression, especially in contrast sensitivity and color vision, others began to show improvements after the third month. The first complete clinical examination to the patients was performed in China a month after the procedure. Successive ophthalmic examinations before the one-year clinical trial will be performed in Argentina following the Chinese schedule by the neuro-ophthalmologist Dra. Alejandra Antacle. She evaluated patients on the day of arrival in Argentina, and on the first, second, third and sixth month after the arrival. Now we are close to the one-year control. In addition, she has conducted the laboratory controls requested by the researchers to quantify therapeutic viruses in blood, with negative results in all cases.

With respect to the visual progression of the boys, it has been excellent, all improved, of course, relative to the degree of the initial condition. From the first seven boys, two of those had almost total blindness; one, in particular, had almost no sensitivity to light. After the intervention, one of the two progressed to approximately 0.3 visual acuity, and the other that had a superior visual loss, in the present can closely identify the first lines of the Snellen test. Additionally, he sees differences in the perception of silhouettes and identifies people’s clothes, a considerable visual advance.

About the other five patients, all had very low vision, only one showed acuity of approximately 0.3, the others had less than that. In general, to date, those who had less initial affectation already have normal near vision and improvements in far vision. We still hope to see progress in the visual field but the improvement of patients with respect to the Snellen test has been very important. Other patients who showed greater visual restraints now present a visual acuity of 0.5 – 0.6 which is a clear improvement, although they are mostly adolescents with a clear memory of previous good vision images, they left Argentina with less than 0.1 visual acuity. As I said, each one started from a different place, but the evolution has been very good.

About the patients who traveled in November, all have also experienced significant changes in vision, although one must be aware that less time has passed since the therapy. It is interesting that the non-injected eye is the one that begins to improve, this happens because ganglion cells share the vector that reaches the optic chiasm. Initially, it improves the eye that has not been injected because it is the one that does not suffer inflammation, after 6 months the injected eye starts to improve. Thus, the experience we have been very interesting in that sense.


How has the success of this therapy influenced social, medical and patient associations?

It is relevant to note that these ten Argentine patients were the only non-Chinese representatives to participate in this therapy. Without forgetting the effort involved we value this participation as a very significant achievement. We are happy to have achieved this goal that has greatly improved the quality of life of the patients and look forward to their visual rehabilitation.

The reality is that this experience changed the landscape in the association. The approval of LUXTURNA for the RPE65 gene had already been a very important push in patients regarding the patients’ expectations of treatments for genetic retinal and optical nerve dystrophies. The appearance of this first therapy has had a hinge effect and it gave us the opportunity to enter patients into the LHON clinical trial. Currently, the evolution of the boys is very positive, has been very important for the momentum of the patients and the association.

However, there are more than 300 causative genes of retinal diseases, and it is a long and arduous road to travel, but it is very clear that it is the path that must be followed. For this, it is essential to have a reliable and complete genetic diagnosis because the therapies are gene-specific in most cases. We cannot know what will be the therapy that can benefit a certain patient if we do not have a complete molecular diagnosis.

Therefore, making the diagnosis is an important battle for us, as a patient’s association. We are fighting this battle in different areas, sometimes with the help of governmental funding, others with funding from pharmaceutical companies, but unfortunately, these are exceptions rather than the rule. The real situation is that in most cases the costs of the genetic diagnosis rely purely on the patient. Health agencies, at least in Latin America, have not yet reached a clear position on whether to cover the genetic study, this is a problem because it leaves many patients helpless.

The patient associations work has to get ready the patients for the therapy, the diagnosis of the patients cannot be started after the therapy has been approved, the patients must be ready beforehand. Therefore, it is of the utmost importance that we continue to strive to achieve a genetic diagnosis for all patients. Although the law declares that the costs of the genetic testing will be met by the public health system, it is more than frequent that the patient’s diagnostic odyssey last several years before an accurate diagnosis is attained. The genetic diagnosis ends with this odyssey, because it identifies the pathology, determines the exact origin and allows that patient to be a candidate for therapy if therapy for the causative gene appears.


The Stargardt APNES experience with LHON therapy is a success and an example. Are you planning to apply this same experience for other types of gene therapies?

Thanks to the work, we have done in recent years; we have almost 600 patients with define molecular diagnosis, which means that we have 600 people who could enter into a clinical trial, of course, if they meet the inclusion criteria. This means that we are in a position to seek admission of our patients to the different clinical trials that are progressing at this moment. For example, this year there are advanced trials in achromatopsia, choroideremia, and retinitis pigmentosa X-linked. This opens a completely different picture for the patient, in all cases we need to have the diagnosis of the patient. We already have many sequenced and we will continue working to achieve the study of many more.

With this horizon, the objective is not to rest on our laurels, we are very happy to have been able to include these ten children, but they are the first ten of many, in reality, there are many people waiting. Our goal is that everyone can have access, first, to the precise genetic diagnosis and that this allows them to access the therapies indicated in each case.

Our goal as an association is to accompany each patient. APNES was formed by parents of children affected with, in particular, Stargardt’s disease, but we work with all the genetic retinal dystrophies. A lot is at stake here, not only the situation of our own children but also that of many more patients. We will continue working in this line and the idea is to enroll as many patients as possible in clinical trials, provided they meet all biosafety and bioethics criteria.

I wish to highlight the enormous help with respect to molecular diagnosis that Dr. Roser González Duarte and her team have done, the most of our patients have been diagnosed by them and have the possibility to access to therapies as these ten children have had. We are very grateful, clearly, it is a huge effort, but it is important to continue on this path and I believe that this is the work ahead. With complete databases, retinal dystrophies are no longer an entity that lacks treatment, because at this point there are solutions on the horizon. The number of advances increases very rapidly, we are very happy, and although we have a lot of work going forward, we have to do it.


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