Blind World

FFB Sponsored Meeting Provides Glimpse of Gene Therapy's Future.

November, 2003.
Foundation Fighting Blindness (FFB).

"On October 21-23, The Foundation Fighting Blindness cosponsored a scientific meeting with The Novartis Foundation called “Retinal Dystrophies: Functional Genomics to Gene Therapy.”"

This meeting brought an international cadre of elite vision researchers together to discuss the current status of genetic research and gene therapy and to identify next steps in this critical research area. Many of the researchers in attendance receive Foundation support to conduct the research discussed at the meeting.

Functional Genomics.

As the name of the meeting implied, two intermeshed research topics—functional genomics and gene therapy—were considered.

Functional genomics is the study of gene function and the molecular and cellular consequences of disease-causing genetic mutations. Once a mutant gene is discovered, functional genomics becomes the next step in the process of developing treatments and cures. The success of gene therapy and other treatments hinges on the ability of scientists to determine how a gene and its protein product interact in retinal cells. Researchers from various Foundation-supported labs presented recent, unpublished findings evaluating gene function in a number of diseases, including Stargardt disease and dominant and recessive forms of retinitis pigmentosa.

Microarray Analysis.

Researchers also evaluated initial results from an emerging and powerful research tool called microarray analysis. Microarray analysis technology allows researchers to better understand the consequences of disease-causing genetic mutations. By placing gene sequences onto a specially designed wafer made of quartz, called a gene chip, researchers can use computers to read the gene chip and analyze the simultaneous expression of thousands of genes.

Researchers are using microarray technology to evaluate gene expression in healthy and diseased retinas. In this way, the patterns of gene expression can be compared to determine the downstream effects of a genetic mutation. Such information will allow researchers to identify genes that interact with a mutant gene, identify genes that may ameliorate the consequences of a gene mutation, and evaluate gene expression associated with cell death.

Results from these studies will help immeasurably in developing treatments. Currently, there is considerable work to create these gene chips and to calibrate the variation of gene expression among normal, age-matched human samples. Once the range of expression in normal samples is better understood, they can be accurately compared with diseased samples.

Gene Therapy.

The second part of the FFB/Novartis Foundation meeting evaluated gene therapy in the treatment of retinal degenerative diseases. By delivering healthy genes or genetic information to cells adversely affected by disease-causing genetic mutations, researchers may very well be able to correct most genetic conditions that cause vision loss.

The dramatic restoration of vision in dogs born blind due to the same gene defect that causes Leber congenital amaurosis (LCA) in humans has spurred researchers to determine what additional steps are needed to advance gene therapy to clinical trials for the entire spectrum of retinal degenerative disease.


Gene delivery systems, or vectors, are central to developing safe and effective gene therapy treatments. Vectors act like a fleet of microscopic delivery trucks transporting genes into retinal cells. Most vectors are derived from viruses. Viruses are extremely effective at infiltrating the nucleus of a cell where genes reside. Over the past decade, Foundation researchers have been working to genetically modify viruses to eliminate their harmful qualities without compromising their delivery capabilities.

In addition to delivering a gene to cells, vectors must be further modified to target only the specific cell type that is affected by disease. For example, the RPE 65 gene, which contains mutations causing LCA, is expressed only in RPE cells. However, the vector used in the restoring vision in dogs born blind from LCA targets photoreceptor cells as well as RPE cells. Fortunately, the abnormal expression of the RPE 65 gene in photoreceptor cells from the gene therapy treatment does not seemingly cause harmful side effects in the dogs. Nonetheless, for human clinical trials, the vector will need to be improved so that it targets only the diseased RPE cell layer. Currently, researchers are developing a more selective vector that targets only RPE cells.

In diseases that arise from gene mutations that are active in photoreceptor cells, gene therapy treatment has been short-lived and less robust. These results are thought to be due in part to the lack of a potent but safe vector that can integrate with photoreceptor cells to give long-term gene expression. Additionally, some photoreceptor cell genes are very large and cannot easily fit into the vector. Researchers at the conference discussed vector design and the use of new vectors, such as lentiviral vectors, that may confer an advantage in photoreceptor cell gene therapy.

Immune Privilege.

Because of the blood-retinal barrier, the retina is thought to be somewhat protected from the body’s immune system. Nonetheless, introducing a vector into the retina may provoke the body’s immune system. This concern may be more heightened in diseases like wet macular degeneration, where blood vessel growth compromises the blood/retina barrier and exposes the retina to the immune system. Further study is needed to determine the immune consequences of gene therapy in a variety of diseases.


In order to test gene therapy in humans, researchers will need to tightly regulate the gene’s expression to insure that it does not over or under produce the resultant protein. Also, further work is needed to make sure that gene therapy treatments do not activate other genes in the retina that would cause harmful side effects. If complications occur, it may become necessary to turn off the gene’s expression. Researchers at the conference discussed various ways to regulate gene expression, including the use of an inducible promoter, which acts like an “on” and “off” switch to control gene expression.

LCA Gene Therapy Update.

More than 24 months after treatment, Lancelot and his littermates continue to see well. Objective measurements with electroretinogram (ERG) tests reveal no loss of visual function. With the success of this initial experiment, Foundation-supported researchers next tested the treatment in animals from different litters, delaying treatment for up to 11 months. All of the treated dogs experienced visual improvement. Although further work is needed, these experiments suggest that a window of opportunity exists to treat older LCA patients. Obviously, these results bode well for Food and Drug Administration (FDA) approval to begin clinical trials.

In addition to the pre-clinical studies described above, researchers must produce the vector to be used in humans under stringent FDA guidelines. Researchers are currently working to develop more suitable vectors for targeting RPE cells. Once complete, vector production for human clinical trials can begin.

Other Diseases.

Genvec, a biotech company in Gaithersburg, MD, is seeking FDA approval to begin human clinical trials testing a gene therapy treatment for the wet form of macular degeneration. With support from The Foundation Fighting Blindness, researchers from Columbia University have launched an effort to test a gene therapy treatment in an animal model of Stargardt disease. A newly formed research consortium is evaluating the feasibility of intervening with gene therapy in Usher syndrome.

In the last year, Foundation researchers have characterized a dominant and X-linked form of RP in dogs. A third breed that exhibits a recessive form of RP now gives researchers an opportunity to test gene therapy in a wide array of RP. Additionally, despite the lack of an animal model, researchers at the University of Pennsylvania are evaluating the feasibility of gene therapy in choroideremia.

How Soon to Clinical Trials?

The Foundation and its researchers are working hard to advance gene therapy treatments to clinical trials. However, it is difficult to predict just how soon treatments will be available. In the case of gene therapy for LCA, researchers hope to begin a phase one clinical trial within the next five years. Other diseases must first show efficacy in animal models to contemplate clinical trials.

The potential of gene therapy in the treatment of genetic disease is enormous. For the first time in our history, we possess the ability to treat and possibly cure these diseases. The faster we can fund all of this deserving work, the more quickly we can realize our urgent mission.

Lastly, The Foundation expresses its heartfelt thanks to Dr. Shomi Bhattacharya from The Foundation’s Research Center at the Institute of Ophthalmology in London for organizing this meeting. The Foundation also thanks the staff of the Novartis Foundation for co-sponsoring a very useful scientific meeting that will serve as a scientific road map for the foreseeable future.

©2003 Foundation Fighting Blindness. All rights reserved.

Go to ...

Top of Page.

Previous Page.

List of Categories.

Home Page.

Blind World Website
Designed and Maintained by:
George Cassell
All Rights Reserved.

Copyright Notice
and Disclaimer.