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Project Title:
Development of an Enzyme Replacement Therapy for Primary Congenital Glaucoma
Principle Investigator:
Rachida Bouhennni, PhD
Institution:
Akron Children’s Hospital
Lay Summary
Glaucoma is a group of diseases that damage the eye’s optic nerve and can lead to vision loss and blindness. Elevated eye pressure from improper drainage of aqueous humor (AH) is the main risk factor for glaucoma. In primary congenital glaucoma (PCG), children are born with a trabecular meshwork (TM) defect that slows AH drainage.
A mutation in the cytochrome p450 B1 (CYP1B1) gene causes the disease. Researchers do not yet know the gene’s function, but they believe it helps process vitamin A in the eye. Because PCG results from a defective enzyme, we hypothesize that replacing the defective enzyme could rescue the phenotype. The long-term goal of this proposal is to develop an enzyme replacement therapy for PCG.
Professional Summary
Primary Congenital Glaucoma (PCG) is a rare inherited recessive disease caused mainly by CYP1B1 gene mutations. PCG produces developmental defects in the trabecular meshwork and anterior segment, raising intraocular pressure and damaging the optic nerve. If doctors do not treat PCG, it can cause blindness. Doctors primarily perform surgery to treat PCG as early as possible.
Although, success of the surgery is relatively good in lowering IOP, complications are common requiring additional surgeries or placement of drainage devices. Additionally, the current medical therapies are not effective in lowering IOP because of the significant anatomical anomaly of the mal-developed anterior drainage angle in PCG patients. Therefore, there is an urgent need for a safer non–surgical approach to treat these patients.
The long term goal of this project is to develop an enzyme replacement therapy (ERT) using recombinant CYP1B1 to treat PCG. We have previously shown that mutations in CYP1B1 leads to accumulation of all trans retinal resulting in activation of p53 leading to growth arrest. Our central hypothesis is that replacement of the deficient enzyme with an exogenous enzyme injected into the eye in PCG will treat the disease by eliminating all trans retinal in the trabecular meshwork thus reducing oxidative stress and the subsequent growth arrest.
To test the central hypothesis, we will assess the efficacy of a local injection of recombinant CYP1B1 in vivo for correcting PCG in a mouse model. Furthermore, this proposal investigates a novel and innovative therapeutic strategy of replacing defective CYP1B1 in PCG. Consequently, these studies present a promising new approach that researchers have not yet fully explored for treating PCG. Therefore, doctors critically need a readily available, effective, and safe alternative method to improve patient outcomes and enhance quality of life for children with PCG.