PUBLICATION
Gene therapy for RAB28: What can we learn from zebrafish?
- Authors
- Moran, A.L., Fehilly, J.D., Blacque, O., Kennedy, B.N.
- ID
- ZDB-PUB-230616-35
- Date
- 2023
- Source
- Vision Research 210: 108270108270 (Journal)
- Registered Authors
- Kennedy, Breandan N.
- Keywords
- Cone-rod dystrophy, Gene therapy, Inherited retinal degeneration, Outer segment phagocytosis, Pre-clinical model, Rab28, Zebrafish
- MeSH Terms
-
- Animals
- Genetic Therapy
- Humans
- Retinal Cone Photoreceptor Cells/metabolism
- Retinal Degeneration*/genetics
- Retinal Degeneration*/therapy
- Retinitis Pigmentosa*
- Zebrafish/genetics
- rab GTP-Binding Proteins/genetics
- rab GTP-Binding Proteins/metabolism
- PubMed
- 37321111 Full text @ Vision Res.
Citation
Moran, A.L., Fehilly, J.D., Blacque, O., Kennedy, B.N. (2023) Gene therapy for RAB28: What can we learn from zebrafish?. Vision Research. 210:108270108270.
Abstract
The eye is particularly suited to gene therapy due to its accessibility, immunoprivileged state and compartmentalised structure. Indeed, many clinical trials are underway for therapeutic gene strategies for inherited retinal degenerations (IRDs). However, as there are currently 281 genes associated with IRD, there is still a large unmet need for effective therapies for the majority of IRD-causing genes. In humans, RAB28 null and hypomorphic alleles cause autosomal recessive cone-rod dystrophy (arCORD). Previous work demonstrated that restoring wild type zebrafish Rab28 via germline transgenesis, specifically in cone photoreceptors, is sufficient to rescue the defects in outer segment phagocytosis (OSP) observed in zebrafish rab28-/- knockouts (KO). This rescue suggests that gene therapy for RAB28-associated CORD may be successful by RAB28 gene restoration to cones. It also inspired us to critically consider the scenarios in which zebrafish can provide informative preclinical data for development of gene therapies. Thus, this review focuses on RAB28 biology and disease, and delves into both the opportunities and limitations of using zebrafish as a model for both gene therapy development and as a diagnostic tool for patient variants of unknown significance (VUS).
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping