UCLA researchers from the Department of Human Genetics and Department of Ophthalmology have developed a mini gene encoding a protein which is mutated in macular corneal dystrophy, leading to a potential gene therapy for this disorder.
BACKGROUND: Macular corneal dystrophy (MCD) is a rare genetic disease caused by mutations in the CHST6 gene, which codes for a protein called carbohydrate sulfotransferase 6. This mutation leads to the loss of clarity of the cornea, which can lead to severe vision loss. There are currently no means of preventing corneal clouding or restoring clarity of the cloudy cornea in individuals affected with MCD, with the only means of improving vision in affected individuals being corneal transplant surgery. Gene therapy, a rapidly growing field, aims to fix a nonfunctional or mutated gene by replacing it with a functional gene. The healthy gene can be transmitted to the patient in a variety of ways, including bacterial or viral vectors, or even by directly editing the human gene. There are several gene therapies in clinical trials for inherited and acquired disorders of the eye, such as age-related macular degeneration, however, there are no gene therapies for inherited disorders of the cornea. Thus, creating a gene therapy targeting the loss of the CHST6 gene in MCD may allow for a non-invasive disease treatment that does not require corneal transplantation, and thus avoids the associated risks.
INNOVATION: UCLA researchers have created a mini gene that encoding segments of the CHST6 gene, which encodes a protein called carbohydrate sulfotransferase 6 that is mutated in macular corneal dystrophy (MCD). While the native CHST6 gene is too large to be packed into an adeno-associated virus (AAV) vector, the mini gene is small enough to be packaged into an AAV vector, allowing it to be used for gene therapy. This mini gene is driven by the native CHST6 promoter, meaning that the encoded protein will only be expressed in the cells of the cornea in which this protein is normally produced, minimizing off-target effects. The demonstration that this mini gene produces a functional protein provides compelling evidence that it may be able to be used to treat MCD, providing a significant advantage over current invasive, non-curative treatments.
POTENTIAL APPLICATIONS:
- Gene therapy for macular corneal dystrophy
ADVANTAGES:
- This mini gene is driven by the native promoter, leading to expression of the protein only in the target cells with constitutive levels of expression for reduced off-target effects
- Gene therapy can address the root cause of the pathology, unlike other treatments (like corneal transplantation)
- Gene therapy is significantly less invasive and fewer potential complications as compared to corneal transplant surgery
DEVELOPMENT-TO-DATE: UCLA researchers have developed a mini gene for CHST6, a gene in which mutations cause macular corneal dystrophy. This mini gene is small enough to be packaged into an AAV vector and is driven by the native gene promoter, ensuring expression only in the cells of interest. This mini gene has the potential to be utilized as a gene therapy for this disease.
KEYWORDS: Macular corneal dystrophy, gene therapy, mini gene, mutation, AAV, native promoter, genetics, keratinocytes, ophthalmology, gene editing