Personalized Medicine: Are We There Yet?

Advances in genetics push ophthalmolgy closer to individualized treatment strategies.

BY SANDEEP GROVER, MD, KHALED K. ABU-AMERO, PHD, FRCPATH

Are we there yet? In our experience with patients with inherited retinal diseases, this question has been asked day in and day out by the multitude with these progressive and untreatable blinding diseases. Most of the time they are told, “You will go blind” and “There is no treatment,” and “There is no use in seeing an eye doctor.”

Almost up to the end of the last century, an infant born with Leber congenital amaurosis (LCA) with profound visual loss and nystagmus would be monitored in the clinic without any hope of treatment. However, in the past decade almost 18 genes have been identified and described, accounting for majority of patients with LCA. In fact, the first human genetic clinical trials in ophthalmology are underway for “gene treatment” for one of the genes (RPE65) that cause LCA, and the results look promising. Does this exemplify how personalized medicine is going to change the way we think about inherited ocular diseases? Here we will offer some answers.

The Past

The British geneticists William Bateson and Reginald Punnett first discovered “genetic linkage technique” in the early 1900s. For some time, this was almost the only technique available for genemapping and identifying genes associated with certain diseases, including many ocular diseases. This technique worked well for familial monogenic diseases. However, because of the nature of the technique, it was not useful for identifying genes associated with multi-gene diseases.

However, this field has progressed rapidly in the last two decades — first with the completion of the Human Genome Project and then, in recent years, the advent of high throughput molecular genetic techniques such as the Genome-Wide Association Study, next generation sequencing and whole-exome sequencing. These techniques have led to the discovery of many genes and single nucleotide polymorphisms (SNPs) associated with various ophthalmic diseases.

One recent example is the discovery of three SNPs associated with primary angle closure glaucoma (PACG).¹ This was the first discovery of a genetic link with an ophthalmic disease once thought to be caused solely by mechanical means involving contact between the iris and trabecular meshwork, which gradually damages the function of the meshwork until it fails to keep pace with aqueous production, and then IOP rises. Certainly, we will start thinking differently about PACG now that a known genetic marker exists for which it can be tested.

Monogenic vs. Polygenic Eye Diseases

Monogenic eye disorders comprise a clinically and genetically heterogeneous group of conditions in which a specific gene defect leads to abnormal structure or function of the eye. The main monogenic eye disorders that cause visual impairment globally are retinal dystrophies, corneal dystrophies, congenital and juvenile cataracts, aniridia and albinism.² In some conditions like Marfan syndrome or von Hippel-Lindau (VHL) disease, the disease is not confined to the eye but involves additional multi-system involvement.

Detecting for mutations in monogenic eye diseases is usually easily performed utilizing Sanger sequencing methods. In some cases, accurately identifying responsible mutations can predict disease development with high accuracy. However, such monongenic eye-diseases tend to be fairly rare.

Polygenic eye diseases, such as macular degeneration and glaucoma, on the other hand, are more common than their monogenic counterparts. They usually involve two or more genes interacting together. Up until recently, the genetic testing technology was laborious, costly and performed in specialized laboratories and under research basis rather than commercialized diagnostic services. However, the advent of technologies such as “next-generation sequencing,” in which multiple genes and larger areas of the genes can be tested simultaneously and efficiently, is changing the face of genetic testing.

Fundus photograph of a child with clinical diagnosis of Leber congenital amaurosis. Genetic testing is indicated to possibly ascertain the gene defect.

The Present State of Genetics

Apart from advances in genetic testing, other fields with application in personalized medicine have seen growth, too. They include:

► Proteomics, which involves identification of proteins associated with genes.

► Metabolomics, the study of the cellular chemical processes.

► Pharmacogenetics, the study of how genes can influence the response to certain pharmaceutical agents in different individuals.

It is not impossible to envision the next era when clinicians “profile” individuals based on genes and proteins, and “tailor” theirmedical treatment to suit the individual profile. But the question to ask is: Are we ready for a new era of personalized medicine in ophthalmology? Like any technology, there are pros and cons for such advancement.

Genetic testing in ophthalmology has definite clinical utility for confirming diagnoses and providing prognoses, possibly decreased morbidity and mortality through preventive care and better treatment options in the future, thus improving patient care and genetic counseling. Molecular diagnosis is becoming increasingly important and will continue to do so with the development of genotype-specific novel treatments. This will happen as new technologies, such as microarray, become available, and as we expand our knowledge of genes associated with susceptibility to complex disorders.

An Array of Questions

Obtaining information about an individual’s genetic make-up is relatively easy, but how we utilize the results begs several questions. Who should pay for these tests — the individual or the insurance companies? Apart from the individual, who should have access to the results—the ophthalmologist, the insurer, the employer? Once results are available, who should interpret the results for the individual — the genetic testing laboratory, the ophthalmologist, clinical geneticist or the genetic counselor? How should insurers or employers use the information? Can testing have a negative impact on an individual whose genotype is positive for a certain disease but does not have the disease yet? What are the social and emotional implications? How would the information impact career choices? Does genotyping have a utility when the condition has no treatment?

“Genetic discrimination” is another fear for patients participating in genetic research. Although the Genetic Information Nondiscrimination Act (GINA) of 2008 protects patients against discrimination in employment and health insurance, legal loopholes exist. Moreover, GINA does not protect an individual fromdiscrimination for being denied disability and life insurance.

Clearly, a step-wise approach is needed for the available genetic information to become practically useful. Many commercial companies are performing “whole-exome sequencing” and “parallel testing of genetic loci.” They are marketing direct-to-consumer genetic tests. Although the latter provides the genetic information to the individual, they carry no responsibility for interpreting results and counseling the individual or family.

AAO Stance on Genetic Testing

Hence, the AAO last year came out with recommendations (2012) 3 based on its Task Force on Genetic Testing. Most of the recommendations try to address the previously mentioned questions. Among the recommendations are:

► A specialist ophthalmologist with knowledge of the genotype-phenotype correlation and who knows best which gene defect to look for should request genetic tests.

► All genetic testing should preferably be performed at Clinical Laboratories Improvement Amendments (CLIA)-approved labs, which will provide not only the genetic variants but also estimates of the pathogenecity of those genetic variants whether they are disease-causing or not.

► In turn, if the specialist has an understanding of the test results, he or she needs to perform the genetic counseling. Otherwise, genetic counselors or medical geneticists should provide genetic counseling.

► Because no treatments exist for most inherited eye diseases, asymptomatic minors typically should not undergo gene testing for now.

► The Academy discourages testing for polygenic diseases, such as AMD, because no specific treatment exists for these conditions.

As we move to an era of personalized medicine in ophthalmology, all patients with genetic eye conditions should have access to ophthalmological specialists who have knowledge and experience in the diagnosis of these conditions. The specialists should be able to counsel patients and families about the advantages and pitfalls of genetic testing.

Some insurance carriers will cover genetic testing; otherwise the patient will have to pay for it. Multiple resources are available for the ophthalmologist and the patient for gene testing and counseling (box). Gene testing at the National Eye Institute (Eyegene test) is free and the NEI sends the results to the requesting specialist.

Care of the individual patient who undergoes genetic testing and counseling involves a care team comprised of the ophthalmologist, the gene-testing lab, genetic counselors and geneticists. The ophthalmologist may play a major role in coordinating the care team.

More Affordable Future

Sequencing of the entire human genome will become more affordable. Genetic testing will become standard of care and insurance carriers will cover the tests. Lawmakers will have to protect the privacy of patients with regards to the results of genetic testing.

Present collaboration between ophthalmologists, researchers, pharmaceutical companies, FDA and lawmakers will result in finding medical and surgical therapeutic options for these conditions in the future. Treatment will be suited and tailored to an individual’s genetic “profile” and ocular condition. Preventive medicine will play a larger role in the future.We can give our patients more hope today that tomorrow will be much brighter. OM

References

1. Vithana EN, Khor CC, Qiao C, et al. Genome-wide association analyses identify three new susceptibility loci for primary angle-closure glaucoma. Nat Genet 2012;44:1142-1146.

2. Johnson GL, Weale R, Minassian DC. The Epidemiology of Eye Disease. Second ed. Arnold Publishers: London, 2003.

3. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases – Report of the American Academy of Ophthalmology Task Force on genetic testing. Ophthalmology 2012;119:2408-2410.

Sandeep Grover, MD, (top) is assistant professor, associate director of the Ophthalmology Residency Program and director of Inherited Retinal Diseases and Electrophysiology at the University of Florida College of Medicine, Jacksonville. Khaled K. Abu-Amero, PhD, FRCPath, is associate professor of medical genetics and head of the Ophthalmic Genetics Laboratory at the Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia. Neither have any financial relationships to disclose.