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National Glaucoma Research
Current Award

Dr. Curtis  Brandt

Curtis Brandt, Ph.D., FARVO

Board of Regents of the University of Wisconsin System, School of Medicine and Public Health
Madison, WI

Title: Enhancement of Gene Expression for Glaucoma Therapy
Non-Technical Title: An Improved Gene Delivery Method to Lower Eye Pressure in Primate Eyes

Co-PI(s):
Paul Kaufman, M.D.
University of Wisconsin-Madison

Duration: July 1, 2013 - June 30, 2015
Award Type: Standard
Award Amount: $100,000

Summary:

Gene therapy to lower intraocular (eye) pressure is an approach for long-term glaucoma therapy that has the advantage of reducing the number of treatments, thereby improving patient compliance. Drs. Brandt and Kaufman wish to use viral vectors (a disabled virus capable of carrying/transporting genes) to deliver these genes to the front part of the eye where eye pressure is regulated. However, there are factors that limit the ability to produce the desired effect, the reproducibility of the delivery, and, ultimately, the expression of the desired gene. Drs. Brandt and Kaufman will use several approaches to overcome these limitations in order to advance the development of glaucoma gene therapy techniques.

Details:

The ability to deliver a gene into cells in the eye holds great promise for the treatment of glaucoma. The most common way to deliver a gene is to use a modified virus, called a viral vector, where the potentially dangerous viral genes have been removed and replaced with the therapeutic gene, using the remaining virus machinery to deliver the desired gene into the cell. Disabled viral vectors related to HIV have a number of advantages in delivering genes to cells in the eye. However, one hurdle to using these types of vectors is that human eye cells have inborn ways to block the delivery of the gene. They do this by recognizing the outer shell of the vector and destroying the incoming virus in several ways. This can either prevent the delivery altogether, or reduce the number of cells that have acquired the gene, and this, in turn, will reduce the therapeutic effect.

Drs. Brandt and Kaufman are testing the hypothesis that interfering with these infection resistance mechanisms will increase the efficiency of gene delivery and enhance the therapeutic effect. They have constructed a viral vector that expresses a protein (called green fluorescent protein) that causes cells to glow a green color, which will be handy to determine the efficiency of gene delivery to the cells that are involved in regulating pressure in the eye. They will use drugs that specifically block the activity of the proteins used to destroy incoming viral particles. In addition, Drs. Brandt and Kaufman will use versions of the anti-infection proteins that act in a “dominant-negative” manner (to prevent them from binding to the incoming virus particles), and they will use “decoy” viral particles to saturate the resistance systems. The studies will first be done with cells grown in culture, and then be tested in an eye organ culture system that more closely mimics the living eye.

When this study is complete, Drs. Brandt and Kaufman will have defined one or more methods to increase the efficiency of gene delivery to cells involved in regulating eye pressure. This will represent an important step in developing gene therapy approaches for treating glaucoma. The next step will be to test several different genes for their ability to lower pressure in the eye and ultimately move the most effective gene therapy candidates forward into clinical trials.

Investigator Biography:

Dr. Brandt is a Professor of Ophthalmology and Visual Sciences at the University of Wisconsin School of Medicine and Public Health. He received BS and MS degrees from Washington State University and M. Phil and Ph.D. degrees from Columbia University in New York City. Dr. Brandt’s laboratory focuses on using viral gene delivery vectors to treat ocular diseases, antiviral drug development and testing, and understanding how viruses cause ocular infections. He has served as Vice Chair for Research in the department and is currently director of the Vision Research Core at the University of Wisconsin-Madison. He has received numerous awards and in 2011 he was named a Fellow of the Association for Research in Vision and Ophthalmology (ARVO).

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