During the 1970s, when the Foundation first began funding retinal disease research, scientists suspected that genetics played a key role in the development of many retinal degenerative diseases (RDDs). In the early 1980s, researchers reported the first gene linkage to an RDD. And, in the late 1980s, the first RDD gene, rhodopsin, was discovered. Today, thanks to significant financial investment, hard work, and innovations in genetic technologies, 158 RDD genes have been identified. Most excitingly, as a result of the highly successful, sight-giving gene therapy tested on 40 blind dogs- one of whom was the famous Briard named Lancelot- we are about to embark on the first human trial of gene therapy to treat the RDD known as Leber's congenital amaurosis (LCA). This landmark Phase I clinical trial is scheduled to begin in fall 2005. FFB is delighted by the significant progress we've helped make possible through genetic research funding- an endeavor that is critical to the treatment and cure of RDDs.
Why genes are important?
Though gene discovery and therapy is not the only path to protecting and restoring vision in people affected by RDDs, it is an essential one. Why? Because abnormalities in genes are the primary, underlying cause of retinitis pigmentosa (RP), Usher syndrome, and Stargardt disease, and they appear to be a factor in determining who will develop age-related macular degeneration. By identifying the genetic abnormalities that cause retinal degenerative diseases, and understanding what the genes do - or don’t do - to cause vision loss, the scientific and medical communities can develop effective treatments, cures, and preventions.
Biologically speaking, genes are important, because they provide instructions to virtually every cell in the body. The instructions sent from genes tell each cell in the body what proteins to make. These proteins are the building blocks of the body. So, if a gene delivers the wrong instructions- or no instructions at all- changes or problems can occur, including retinal degenerative disease.
When a gene doesn't do what it is supposed to do- when it doesn't give out the right instructions (or it gives out no instructions)- it is said to be mutated. Genetic mutations in RP can be particularly challenging for researchers, because they don't necessarily appear or behave in consistent or orderly ways. For instance, different mutations in the same gene may lead to different outcomes in different patients. Alternatively, mutations in different genes may cause the same disease.
The human body has approximately 30,000 genes, and virtually every cell in the body has a copy of all 30,000 genes. People get their genes from their parents- half from their mother and half from their father. For comprehensive introductory information about genetics, download FFB's booklet, The Inheritance of Retinal Degenerations.
Many achievements, but much work remains
The discovery of 158 RDD-related genes over the past 15 years is phenomenal progress. The discovery of each new gene has given researchers a new foothold in their efforts to cure and treat RDDs. However, the identification of new genes- though essential to treatment progress- is not a simple task. It takes powerful and expensive technology, the collection of extensive genetic histories of patients and families, and a lot of leg work.
In addition, though a large number of RDD-related genes have been found, scientists believe there are many more that have yet to be discovered. The best measurement of progress in gene discovery may be in the following statement: When a person is diagnosed with retinitis pigmentosa (RP), there is about a 50% chance that the RP gene(s) can be identified. But, that also means that today 50% of the people who have RP can't pin down their condition to a specific gene(s). The process of identifying specific genes in a person or animal is called genotyping.
It is important to understand that RP is a family of diseases caused by a large number of different genes. In many cases of RP, for example, multiple genes play a role in a specific incidence of RP in an individual.
The varying manifestations of RP are called phenotypes. A person's phenotype is how their genes affect their vision and other physical characteristics. A phenotype for someone with RP is defined by: when their vision loss began, how quickly it progressed, what type of vision is affected, and other ways that the genetic mutation(s) affected them.
Researchers have learned that in some instances, even normal genes can influence the effect mutated genes will have on a phenotype. In other words, two people from the same family (e.g., siblings) with the same RP mutations may experience completely different rates and severity of disease symptoms.
The range of symptoms may be as wide as no vision impairment to major vision loss.
Scientists are very interested in mapping genotypes with phenotypes. That is, they want to see how a person's genotype, their genetic make-up, leads to the progress and magnitude of their retinal disease. Read the article, FFB Grant Center at the University of Iowa, in this issue of InSight to learn how the development of a genotype-phenotype database, along with widely available genetic testing, will lead to better treatments for patients.
Though the genetic aspects of RP and other RDDs are complex, researchers are enthusiastic and encouraged about finding cures and treatments, because of the vast amount of knowledge they've accumulated over many years of work. In fact, they find themselves on the leading edge of genetics and gene therapy. Scientists studying neurological diseases are closely watching the breakthroughs in RDD research. Because the retina is considered to be part of the central nervous system, and it is far more accessible than the brain, it is easier to test new therapies in the retina rather than in the brain or in other neurological regions. Researchers hope to take the lessons learned in retinal treatments and apply them to the treatment of other neurological diseases.
Major breakthrough in gene therapy
The most promising approach to gene therapy thus far has been the use of a human-engineered virus to deliver new genes and treatments to cells in the retina. These man-made viruses are known as viral vectors. In particular, a virus called the recombinant adeno-associated virus (rAAV) has been an effective delivery mechanism for genetic treatments. The rAAV vector can penetrate the retina, it can be targeted to specific cells, and it has proven to be relatively safe.
The rAAV vector was used to deliver gene treatment to 40 blind Briard dogs- including Lancelot and his siblings - who has a mutated gene called RPE65, the same gene mutation that causes Leber's congenital amaurosis (LCA) in humans. After a single injection, which was administered four years ago, the dogs still have excellent vision. As stated previously, this same vector therapy will be tested in a human, Phase I clinical trial in fall 2005.
One must keep in mind that RPE65 gene therapy is only effective for treating one type of LCA. There are other types of LCA caused by mutations in other genes, and LCA is only one type of RP. Treating the mutated genes of other forms of RP won't necessarily be as simple as the RPE65 therapy. However, the rAAV vector, if proven to be safe and effective in humans, should be a useful therapy delivery mechanism for many types of RP. It is a major step forward in RP treatment.
Success with survival factors
Though the genetics involved in RP and other RDDs is complex, there is good news in the fact that researchers have learned that many different forms of RP involve similar cellular pathways for progression of the disease. In other words, though numerous genes cause many types of RP, there are just a few mechanisms that actually cause vision loss. So, by treating these downstream mechanisms, researchers are hopeful they can prevent vision loss for many or a majority of people who have RP.
The most common cellular pathway leading to vision loss is a process of programmed cell death called apoptosis. When photoreceptor (PR) cells (the rods and cones that provide vision) don't get the right proteins or nutrition, or if they can’t dispose of toxic waste products properly, they go through apoptosis. When rod and cone cells die, vision is lost.
Researchers have identified certain proteins- known as survival factors- which can help prevent apoptosis. One such factor- ciliary neurotrophic factor (CNTF)- is being tested in a human, Phase I clinical trial.
In this study, researchers implanted a tiny device called encapsulated cell technology (ECT) in the eye. The ECT contains genetically modified retinal pigment epithelial (RPE) cells, which provide sustained release of CNTF. In animal studies, the sustained release of CNTF was effective in preventing apoptosis and vision loss.
If the Phase I trial and subsequent trials of CNTF therapy go well, people with many types of RP will have an effective treatment to slow vision loss.
Overview of other genetic breakthroughs
► FFB-funded Researchers from the University of California, San Diego, and the University of California, Los Angeles, are working on a gene therapy in a mouse model of Usher 1B. They are attempting to replace the mutated gene with a normal version.
► A mouse model of Usher 1C was found by FFB-funded researchers at the Jackson Laboratory in Bar Harbor, Maine. They discovered the model by examining mice that displayed a head motion often associated with inner ear problems and deafness. The mouse model could be important for studying the cause of the disease, the link between hearing and vision, and gene therapies.
► Another FFB research team from the University of California, Berkeley, is making important discoveries that may someday lead to a cure for another form of Usher syndrome, Usher 3. Using experience from the Briard-LCA dogs, the researchers are developing a mouse model to safely and effectively deliver a normal gene.
Age-related Macular Degeneration
► Foundation-sponsored researchers from the Casey Eye Institute of Oregon Health & Science University, and their colleagues from other institutions, discovered a gene mutation linked to an age-related macular degeneration (AMD). The mutation was discovered in a family with an unusually large number of people with AMD. The discovery bolsters hope for a therapy to prevent and potentially cure AMD. The gene is called fibulin 6.
► A second and more common gene mutation related to AMD was found by researchers at the FFB-funded Research Center for Macular Degeneration and Allied Retinal Diseases, at the University of Iowa. The gene is called fibulin 5. It is responsible for the production of a protein in fibers of Bruch's membrane, which separates the retina from underlying blood vessels. The researchers hypothesize that the mutation of the fibulin 5 gene could lead to breaks in Bruch's membrane, allowing abnormal, leaky blood vessels to grow beneath the macula, leading to a major loss of vision.
The gene findings in AMD could lead to the development of an animal model of human AMD and to an accelerated search for drugs and other interventions for AMD.
►FFB-funded researchers from the University of Kentucky College of Medicine discovered a mouse type that exhibits an AMD-like condition, providing the first animal model that can show the progression of dry AMD to the wet form.
The researchers believe that this mouse could be key to studying drugs, neurotrophic factors, steroids, and other therapies to prevent wet AMD.
► X-linked juvenile retinoschisis is another in the growing list of severe retinal disorders for which there is now an animal model. Researchers have developed a "knock out" mouse that is deficient in the functional equivalent of the human RS1 gene.
The retinoschisis mouse model is the effort of a team of researchers from the U.S., Germany, and Canada. The Foundation Fighting Blindness is supporting continued collaboration of the team, which is working with the mouse model to replace the retinoschisis gene with a healthy one. It would pave the way for gene therapy trials in humans.
► Researchers from the FFB Research Center at Columbia University College of Physicians and Surgeons are working on gene therapy for treating Stargardt disease. In a mouse model, they are working on efficiently and effectively inserting a healthy version of the ABCA4 gene into photoreceptor cells. Ultimately, the researchers hope to insert a healthy version of the ABCA4 gene into the retina of patients with Stargardt disease.
DISCLAIMER: Physicians differ in their approach to incorporating research results into their clinical practice. You should always consult with and be guided by your Physician’s advice when considering treatment based on research results.