Using tropical fish to develop Gene therapies: what can we learn?
Professor Breandan Kennedy is a vision loss researcher based at University College Dublin (UCD). Fighting Blindness have funded projects led by Prof Kennedy in the past number of years. One of the areas that Prof Kennedy works in is zebrafish and how they can be used to study inherited retinal diseases (IRDs). Below we outline why zebrafish are used in research; this information is from a 2023 scientific review article that came out of a project led by Prof Kennedy in part funded by Fighting Blindness.
From fish to humans, living organisms have the ability to adapt their eyes to light changes and recognize different colours. Cone photoreceptors in the retina play a key role in this, as well as helping us read things in detail like other people’s facial characteristics.
IRDs are rare genetic disorders but also the leading cause of vision loss in people of working age. There are more than 200 genes associated with IRDs and due to this high heterogeneity between different IRD patients, correct diagnosis is complicated.
Cone-rode dystrophies (CORD) are a subgroup of IRDs characterised by:
- problems in colour vision
- eye discomfort in bright light (photophobia)
- difficulties in distinguishing shapes and the details of objects at a given distance (low visual acuity)
- Later the CORD progresses into loss of night and peripheral vision
There are many different types of CORD, which differ in their genetic cause and the way in which they are inherited.
The available therapies for IRDs are limited, with only one gene therapy being available, approved by European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA), called Luxturna (also called voretigene neparvovec-rzyl). Unfortunately, although Luxturna has been life changing for those that have received it, only a small percentage of people affected by Leber congenital amaurosis (LCA) and retinitis pigmentosa are eligible to receive it. Therefore, there is still a high need for IRD therapies to be developed.
Prof. Kennedy’s recent review article describes the use of zebrafish as a model both for the development of gene therapies for IRDs as well as a potential diagnostic tool.
Using a zebrafish- a small tropical fish, to study human inherited diseases might seem paradox, but the article outlines the reasons why we use these fish. These include:
- the zebrafish eye has high similarity with the human eye (76% genetic overlap),
- the zebrafish have highly developed vision due to the need for fast larval visual development and refined visual acuity,
- the high presence of cone photoreceptors makes them the ideal animal model for the study of CORD.
In this review article, the scientists highlight their work on one of the genes found to cause autosomal recessive cone-rod dystrophy (CORD), the RAB28 gene. When a condition is inherited in an autosomal recessive manner, it means that both copies of the RAB28 gene don’t work properly, giving rise to the condition. In this case, the patient’s mother and father have both passed on a mutation, or a DNA change, for the RAB28 gene.
When the genes are mutated, the RAB28 protein cannot be produced leading to the disruption of an important cellular process, called outer segment phagocytosis (OSP). OSP is an essential process for waste removal and recycling within the light-sensing photoreceptors in the eye so that they stay healthy.
The UCD researchers emphasise that restoring the OSP process could be a common target point for treating CORDs and other IRDs. Indeed, they managed to induce the production of the RAB28 protein in the cone cells, and restored the OSP defect in zebrafish models with the genetic RAB28 mutation. Given that there are no clinical trials for the RAB28- related CORD cases, Prof. Kennedy and his team, stress the importance of using zebrafish in order to progress human RAB28 gene therapies.
You can listen below to what one of the Ph.D. researchers involved in the study told us about his lab work and the importance of patient input into research, after he attended our 1st V.I.P. Network (Visual Impaired Persons) Coffee morning in June 2023.
In addition to the therapeutic potential that the study of mutated zebrafish could offer, the current publication also explores the option of using it for diagnostic reasons too. Genome sequencing has been available to patients making it possible to identify which genes cause certain conditions. However, in IRDs due to the high level of genetic heterogeneity, the interpretation of variants (gene mutations) can be very difficult.
When a gene mutation is identified as possibly causing a condition, but not with complete certainty, it is called variant of uncertain significance (VUS). At the moment there is no way to investigate VUS in the RAB28-CORD cases therefore there is need for better diagnostic tools. The scientists suggested the idea of using the zebrafish due to their high similarity with humans in the way the RAB28 mechanism works.
Indeed, using molecular biology tools, they successfully created zebrafish lines expressing human RAB28 genes. These models are being characterised to assess vision, retinal histology, and retinal biochemistry to enable the diagnosis of patients. However, the scientists emphasize that it is yet unknown as whether human RAB28 functions exactly similarly to zebrafish, therefore more investigation is needed.
We spoke to Professor Breandán Kennedy about his project and you can find the interview here.
Moving forward, the researchers hope to expand this platform to other IRD genes as well, while according to Prof. Kennedy this process could increase accessibility to clinical trials for specific IRD genes by informing patients in a more accurate way about the genetic cause of their impaired vision.
Thank you to all the researchers who worked on this study:
Ailis L Moran Ph.D., John D Fehilly Ph.D. candidate, Prof. Oliver Blacque, and Prof. Breandán N Kennedy.
Based at:
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
Sources:
- Click here to find the full information about the publication.
- To learn more about the CORD click here
- To learn more about what a VUS is click here
- To learn about our first V.I.P. coffee morning and join our V.I.P. network click here