A highly effective gene-editing technique developed by researchers at the Institute of Molecular and Clinical Ophthalmology Basel (IOB) could potentially treat Stargardt disease, the most common form of inherited macular degeneration, which can lead to vision loss. In a paper published in the journal Nature Medicine on January 8, the researchers detail the successful application of the base-editing technique, which can correct the most common mutation associated with Stargardt disease.
Among the authors of the study there are several researchers at Semmelweis University; an important part of the experiments was carried out using a special retinal tissue culture from the Retina Laboratory of the Department of Anatomy, Histology and Embryology. The effectiveness of the base-editing technique was demonstrated in human retinal cultures and human retinal pigment epithelial cells, among others. The procedure used in the experiments, which is unique worldwide and enables the survival of retinal tissue harvested from deceased organ donors for up to 35 weeks, had been developed at Semmelweis University by Head of Laboratory Dr. Arnold Szabó.
The research was led by Dr. Bence György of IOB, who, like Dr. Botond Roska, graduated from Semmelweis University. He has been collaborating with the Department of Ophthalmology since his undergraduate years, and he started his research career at Semmelweis’s Department of Genetics, Cell and Immunobiology. As he told our website, base editing, this precision gene-editing technique, involves injecting the base-editing enzyme into the retina using the so-called adeno-associated virus (AAV), a non-pathogenic virus vector system, like a Trojan horse. This “molecular machine” can detect which of the 3 billion base pairs in DNA is defective and correct it. “This impressive precision is essential for the development of a safe and effective therapy,” said Dr. Bence György, Head of the IOB’s Ophthalmic Translational Research Group, who is hopeful that the technology could be applied to patients within a few years.
The researchers tested the technique in seven different models, from cell cultures to human retinal cells. Work of this scale requires several collaborating partners, including Semmelweis University, where the human retina model was tested.
“In probing the newly published base-editing technique in human models, i.e. human retinal cultures artificially fixed in the laboratory, we have tested the IOB-developed viral vectors in several combinations to measure their effectiveness. The fact that the tests were done in real human tissues provides strong evidence for the future applicability of the treatment in patients,” stressed Dr. Arnold Szabó, Head of the Retina Laboratory at the Department of Anatomy, Histology and Embryology at Semmelweis University. He added that Dániel Magda and Ferenc Kilin, who also co-authored the study, had carried out much of the experimental work.
Dr. Botond Roska highlighted that they had been cooperating with Semmelweis University for more than ten years, especially with Dr. Zoltán Zsolt Nagy, Director of the Department of Ophthalmology, and Dr. Arnold Szabó. The research that has led to the publication is also in line with the project by Dr. Botond Roska and the above-mentioned two researchers from Semmelweis University, which has been granted funding in the framework of the National Research, Development and Innovation Office’s Frontline – Research Excellence Programme launched in 2021.
A gene-editing technique similar to the one just published has not yet been used in patients, but a gene therapy intervention using the AAV vector system is already available for another rare eye condition. Ten patients have already been treated at the Department of Ophthalmology of Semmelweis University, which has been a certified ophthalmic gene therapy center since 2022. The results of the AAV vector-based gene therapy are favorable, pointed out Director Dr. Zoltán Zsolt Nagy, who is also one of the authors of the current study. Hopefully, the new therapeutic method will soon be available to patients, so that more ophthalmic genetic defects can be cured, he added.
As the researchers noted in a press release issued by IOB, their base-editing approach could potentially be adapted to treat other inherited retinal diseases caused by similar types of mutations. These results represent a significant advancement in the field of ocular gene therapy.
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The next steps include further safety studies and preparations for clinical trials.
Stargardt disease affects 1 in 6,500 individuals and is the most common form of inherited macular degeneration. It is a hereditary disease, whose symptoms develop at a young age, causing a gradual loss of visual acuity and, eventually, in the majority of cases, legal blindness.
Pálma Dobozi
Translation: Judit Szabados-Dőtsch
Photos by Boglárka Zellei, Attila Kovács – Semmelweis University; Gábor Ancsin, RTL Praxis
