UCLA researchers from the Department of Ophthalmology have developed a novel gene therapy method to treat Congenital Hereditary Endothelial Dystrophy.
BACKGROUND: Congenital Hereditary Endothelial Dystrophy (CHED) is a rare autosomal recessive disease that affects corneal endothelial cells, which can lead to blindness if left untreated. CHED is more frequently observed in regions where consanguinity is prevalent, such as in the Middle East, South Asia, and Southeast Asia, and can cause the cornea to become opaque due to corneal edema (swelling) at or shortly after birth. The primary treatment for CHED is corneal transplantation, which is typically performed in infants and children. However, this procedure carries significant risks, including complications during and after surgery, as well as high rates of transplant rejection and failure. Given that there are no pharmaceutical treatments for CHED, there is an urgent need for alternative therapies to manage and potentially cure this debilitating disease.
INNOVATION: Researchers at UCLA have developed a novel adeno-associated virus (AAV) vector gene therapy for treatment of infants and children with CHED that have a mutation in each copy of the SLC4A11 gene, which encodes a protein important in maintaining the clarity of the cornea. Importantly, 80% of individuals with CHED have mutations in SLC4A11, making it an enticing drug target. The researchers demonstrated that an AAV vector expressing a fluorescent marker that is injected into the stroma of a human cornea obtained from an eye bank could successfully transduce the corneal endothelium. The researchers then tested an AAV vector expressing SLC4A11 and found that (i) it successfully transduced an immortalized human cell line and (ii) the transduced cells produced the mature SLC4A11 protein. The researchers then confirmed that the replacement of SLC4A11 protein in human corneal endothelial cells in which the SLC4A11 protein had been removed successfully restored the primary functions of SLC4A11, specifically NH3/NH4+ and H+ conductance and protection from oxidative stress. The UCLA investigators then tested the efficacy of SLC4A11 gene therapy in vivo in a mouse model of CHED in which the SLC4A11 protein is not expressed. A single intrastromal injection of the AAV vector expressing SLC4A11 in one cornea of each Slc4a11-/- mouse resulted in a significant reduction in the corneal edema when compared to the untreated cornea. The investigators are currently repeating the studies in the mouse model of CHED and are performing a toxicology and biodistribution study using the viral vector produced by the company that will be used for the first-in-human trial of gene therapy for infants and children with CHED.
POTENTIAL APPLICATIONS:
- Early intervention to stop the progression of CHED
- Potential to treat other disorders, such as Harboyan Syndrome, which is also associated with SLC4A11 mutations
ADVANTAGES:
- There is no pharmaceutical treatment currently available for CHED, presenting a significant market opportunity for this drug
- Less invasive than surgery
- No risk of rejection post-inejction as opposed to corneal transplants
- The program was awarded Rare Pediatric Disease Designation and Orphan Drug Designation by the FDA
DEVELOPMENT-TO-DATE: UCLA researchers have constructed an AAV vector expressing SLC4A11 in a laboratory setting to restore the function of this protein when mutated. This AAV vector allowed researchers to restore the compromised protein in both in vitro (using human cells) and in vivo settings (using mice).
Related Papers (from the inventors only)
Kao L, Azimov R, Shao XM, Frausto RF, Abuladze N, Newman D, Aldave AJ and Kurtz I. Multifunctional ion transport properties of human SLC4A11: comparison of the SLC4A11-B and SLC4A11-C variants. Am J Physiol Cell Physiol. 2016; 311:C820-C830.
Zhang W, Frausto R, Chung D, Griffis CG, Kao L, Chen A, Azimov R, Sampath AP, Kurtz I, Aldave A. Energy shortage in human and mouse models of SLC4A11-associated corneal endothelial dystrophies. Invest Ophthalmol Vis Sci. 2020;61:39
Chung DD, Chen AC, Choo CH, Zhang W, Williams D, Griffis CG, Bonezzi P, Jatavallabhula K, Kurtz I, Sampath AP, Aldave AJ. Investigation of the functional impact of CHED- and FECD4-associated SLC4A11 mutations in human corneal endothelial cells. PLOS ONE 2024 Jan 22;19(1):e0296928.
KEYWORDS: Gene therapy, CHED, SLC4A11, corneal endothelial cells, corneal edema, corneal transplantation, adeno-associated virus, biallelic mutation, single-cell patch clamp recordings, intracameral injection, intrastromal injection