Clinicians are beginning to use genetic information in patient management

Retina/Vitreous

Less than a decade ago, the map of the human genome was released and the promise of genetic medicine came to the forefront.

When a working copy of the human genome was published in 2000 (and a nearly complete code in 2003), the scientific community buzzed about the potential to alter the future of medicine. Since that time, the pace of genetic research has hastened, and gene replacement therapy has moved closer to reality.

In a broader sense, however, genetic information is already being used in clinical practice in testing and counseling. With the information mined from early genotype-phenotype correlation studies, ocular geneticists can acquire a genetic profile of a patient, predict the likelihood of developing a sight-limiting condition and encourage lifestyle changes that can reduce the risk of developing the disease.

Epigenetic factors

An important aspect of genetic counseling is to reduce those factors that may enhance the likelihood of a phenotypic expression of an underlying genotypic abnormality. These so-called epigenetic factors do not alter an organism’s genes, but in the presence of genetic mutations, they can lead to the cascade of events that eventually results in a disease expression.

Jerome Sherman

In Leber’s hereditary optic neuropathy, for instance, epidemiologic studies have identified environmental risk factors that contribute to disease expression among individuals with an underlying genetic susceptibility. Certain pesticides, as well as smoking tobacco and consuming alcohol, may trigger the chain of events.

“Those can be reduced, and we believe that by reducing the trigger mechanisms, we are reducing, substantially, the disease itself,” Jerome Sherman, OD, FAAO, a member of the Primary Care Optometry News Editorial Board, said in an interview.

Another condition that has important epigenetic factors is macular degeneration. The genetic susceptibility to developing macular degeneration among individuals with mutations in the code for complement factor H has been well described. Drawing from that, as well as other research on triggers for the complement system, geneticists have identified tobacco smoke as a significant environmental risk in patients with or with the potential to develop macular degeneration.

Michael Tolentino

“One of the reasons smoking is so bad is that it is one of the biggest complement factor activators we have,” PCON Editorial Board member Michael Tolentino, MD, said in an interview. “A puff of smoke activates your complement system.”

Other genetic research on macular degeneration highlights the importance of knowing genetic susceptibility. According to Dr. Tolentino, alterations in the code for three genetic mutations, including complement factor H, may increase the risk of developing macular degeneration, but the risk increases significantly if an individual has mutations at two or all three of the loci.

Several companies are now developing commercially available tests that may identify mutations at these specific loci, which could indicate if intervention is warranted.

“For a condition that you have no way to modulate, that information is useless,” Dr. Tolentino said. “But with macular degeneration, you have several ways of modulating your risk. Macular degeneration is a chronic process. The best time to attack macular degeneration is not when you are full blown, but when you are in your 30s and 40s.”

Gene therapy

Armed with an understanding of the genetic factors leading to macular degeneration, researchers are now attempting to develop novel strategies to address them. However, according to Dr. Tolentino, while true gene replacement therapy is one avenue of research, another approach is “trying to understand what went wrong in patients who have an inherited macular degeneration and what can we do from a drug perspective to address that and hopefully prevent the condition from progressing, maybe even slowing it down, maybe even stopping it.”

In the chain of events leading to macular degeneration, mutated complement factor H promotes the deposition of inflammatory debris, which appear as drusen in the eye. As drusen builds up, it oxidizes and becomes more toxic, so the body promotes neovascularization to bring nutrients to the macular site. However, that neovascularization is indiscriminate, and so new blood vessel growth may unwittingly disrupt retinal architecture, leading to the hallmark functional degradation in macular degeneration.

According to Dr. Tolentino, work now being done at the University of Iowa, led by Gregory S. Hageman, PhD, is attempting to introduce substitute protective factor H early in the disease course, thereby enhancing the body’s natural protection against inflammatory damage.

“That’s not true gene therapy, but you are using genetic knowledge to understand the basic problem and developing therapeutic strategies,” Dr. Tolentino said.

Other strategies in genetic-based therapy involve stopping the complement system, the component of the inflammatory cascade that destroys infectious agents. Functioning factor H protects normal cells from this destructive cascade. It is critical to stop the cascade in a way that will allow destruction of infectious agents while preventing destruction of normal cells.

Diana L. Schechtman

Gene replacement therapy is a potentially viable strategy in other retinal conditions, such as Leber’s congenital amaurosis (LCA) type 2. In 2008, three separate studies demonstrated the safety of locally introducing an RPE65 gene by means of an adeno-associated viral vector in patients with early stage Leber’s. The phase 1 trials demonstrated the safety of the procedure, but also hinted at some limited biological activity: functional vision was restored in some patients.

“The pathogenesis of retinitis pigmentosa is attributed to genetic defects resulting in photoreceptor apoptosis,” Diana L Shechtman, OD, FAAO, said in an interview. “Thus, the future of retinitis pigmentosa will certainly involve genetic therapeutic options.”

She added that while these early results are encouraging, “safety and efficacy have not been well established, and larger well-controlled studies are still necessary.”

Genetic complexity

Gene replacement therapy in LCA type 2 may be a feasible strategy. According to Dr. Tolentino, this replacement therapy will restore function because it replaces a dysfunctional protein involved in vision.

In other retinal degenerations, “The damage becomes permanent, due to the toxic buildup of a mutated protein,” he said. “The retina degenerates. So you can’t give therapy to a patient whose retina is irreversibly damaged and expect that by replenishing or giving back that mutated protein you’re going to get vision back.”

A potential strategy in gene therapy for other retinal degenerations, Dr. Tolentino added, may be a combination of gene suppression and gene replacement; that is, introducing a genetic code that will both block the aberrant code and introduce the correct code sequence, resulting in suppression of toxic proteins and restoring function.

“That combination of therapy is the most promising, but also the most challenging,” Dr. Tolentino said.

The complexity of retinitis pigmentosa highlights that challenge. Researchers have identified between 40 and 100 different genetic mutations that can lead to the development of varying forms of retinitis pigmentosa. However, according to Dr. Shechtman, a large number of cases still have no known genetic cause. It is that vast unknown that limits the potential of genetic intervention.

In fact, the entire human genome involves some 3 billion possible nucleotide sites where an abnormality can occur. It is impractical to think that genetic testing could scan the entire sequence to identify aberrant coding; as well, genotype-phenotype correlation is incomplete for many ocular pathologies, so an entire scan might yield little clinical knowledge.

One way to improve the odds of devising useful genetic information – to be able to offer counseling or to devise drug or genetic strategies – is to first determine in the clinic which patients might have a genetically derived disease. This is something that Dr. Sherman is now investigating in his own research.

“What is really important before you do genetic testing is to have a good clinical profile of the patient,” Dr. Sherman said. “By knowing a lot about the patient, by being able to identify the most probable diseases, the clinician can guide the ophthalmic geneticist to gear the genetic evaluation to look for those particular genes known to be associated with a specific disease.”

While mining for genetic information may not have direct and immediate clinical utility, Dr. Sherman believes that determining genetic susceptibility has additional benefits.

“As a potential treatment becomes available for a specific disease, patients who have been previously diagnosed can be contacted and offered the new therapeutic intervention,” he said.

For more information:

• Jerome Sherman, OD, FAAO, a member of the Editorial Board of Primary Care Optometry News, is the Distinguished Teaching Professor at the State University of New York and in private practice at the Eye Institute and Laser Center. He can be reached at SUNY College of Optometry, 33 West 42nd St., New York, NY 10306; (212) 938-5862; fax: (212) 780-4980; e-mail: jsherman@sunyopt.edu.
• Michael Tolentino, MD, is a Primary Care Optometry News Editorial Board member who practices at the Center for Retina and Macular Disease, 250 Avenue K, SW, Winter Haven, FL 33880; (863) 297-5400; fax: (863) 293-9780; e-mail: miket@crmd.net; Web site: CRMD.net.
• Diana L. Shechtman, OD, FAAO, is an associate professor of optometry at Nova Southeastern University College of Optometry. She can be reached at 3200 S. University Drive, Ft Lauderdale, FL 33328; (954) 262-1827; e-mail: dianashe@nova.edu.