Striving for Visual Clarity in the Genomic Era
Dr. Elise Héon, MD, FRCS(C)
Professor, Department of Ophthalmology and Vision Science, University of Toronto
By: Ranya Barayan & Anjali Vig
Inherited retinal dystrophies are genetically heterogeneous blinding disorders characterized by progressive retinal degeneration (RD). RD affects approximately one in 3,000 individuals and can manifest itself at various ages with variable severity and inheritance.1 Using genetic testing, mutations have been identified in over 200 genes, but these account for at most 60% of cases.2,3 There are only a few common variants which have been found to influence inherited RD and almost all causal mutations are rare.1 As there is no cure for RD, there is a strong incentive to understand its genetic basis to develop therapies that can slow or prevent vision loss, generate better diagnostic tools, and improve quality of life.
To learn about the advances that have been made to better our understanding of RD pathogenesis, we sat down with Dr. Elise Héon, member of the Institute of Medical Science and professor of Ophthalmology with the department of Ophthalmology and Vision Sciences at the University of Toronto. She is also a staff ophthalmologist and director of the Ocular Genetics Program at the Hospital for Sick Children. This program is unique in Canada and one of only a few in the world. Her clinical work focuses on the management of hereditary eye diseases, which include hereditary cancer (retinoblastoma) and other non-cancerous blinding conditions such as retinitis pigmentosa (RP). In addition to her teaching and clinical responsibilities, Dr. Héon is a Clinician-Scientist in the field of Ocular Genetics, and a Senior Associate Scientist at The Hospital for Sick Children Research Institute in the program of Genetics and Genomics Biology. Her laboratory is involved in the genetic analysis of inherited eye disorders with a focus on retinal dystrophies.
Dr. Héon specialized in ophthalmology in medical school at Sherbrooke University, where she quickly became bored with the routine training in cataract surgery. She describes what first inspired her to study rare diseases. “I had encountered a case of rare disease as a resident which, unlike common diseases, could not be treated with prescription-based medicine or surgery, and it was really sad that these patients could not be treated,” Dr. Héon explains. “I believe that there is always a solution. Just because we currently don’t have something that “fits”, it doesn’t mean that a solution doesn’t exist—that there is no hope.”
For this reason, she came to the University of Toronto in 1991 to complete her fellowship with Dr. Maria Musarella, who fostered her interest in the genetics of inherited eye diseases. At that time, only two genes were known: rhodopsin (RHO) and retinal degeneration slow (RDS). If someone found a mutation in a different phenotype, it automatically meant that they had to be wrong, because at that time it was thought that one gene “clearly” meant one phenotype. Not long after, there was a major shift in the whole paradigm of understanding diseases. The ability to clinically phenotype patients expanded as the technical tools continued to improve. Therefore, ophthalmology was in a unique position to phenotype quite precisely. Now, the exact structure and function of over 200 genes have been well-documented.
Dr. Héon’s work focuses on identifying the underlying genetic mechanisms of a variety of inherited ocular diseases. In many cases, the lowest hanging fruit have already been picked, which requires her lab to confront conventional thinking. One of her main projects involves interpreting Whole Genome Sequencing (WGS) data from patients with inherited retinal disease where no disease-causing mutations have been identified by “standard of care” genetic testing. This testing does not fully exploit coding and non-coding regions of the genome, whereas WGS provides the opportunity to dig into these previously unexplored areas. It also gives deeper insight into how phenomena such as transposable DNA elements like retrotransposons, copy number variations, and regulatory elements can influence inherited retinal disease.
However, analyzing WGS data can be challenging because of the immense quantity of information that is produced. Dr. Héon and her lab are continuously learning how to best interpret this data. She emphasizes the importance of collaboration by highlighting that her work is made possible through a collaborative and multidisciplinary approach to research, with a strong network including bioinformatics, epigenetics, cellular biology, structural biology and imaging.
As a part of the WGS project, Dr. Héon’s group is interested in identifying and validating the role that putative disease-causing variants in regulatory and intergenic regions of the genome play in RD. So far, there has only been one association of variants in regulatory regions to retinal degeneration,1 making this an exciting opportunity to highlight the role of regulatory regions in RD. The project will help lay the foundation for future gene discovery and variant interpretation for individuals with unknown causes of RD.
“It is a very emotional process when someone learns that it is likely that their vision will decrease. When patients do not know what they have, they feel alone,” says Dr. Héon. “Providing patients with ‘their gene’ or the variant that is responsible for their RD is an important step in helping them feel less alone. It is important to always find options for the patient, and when patients know that you are trying to make a difference, they trust you.”
To maintain that trust, Dr. Héon stresses the importance of realistic scientific communication that does not overhype the implications of scientific results or provide false hope “Otherwise, donors and patients will not trust scientists anymore and the whole system will be at a loss,”
she explains. “Playing ‘hero race’ is a big mistake, because at the end of the day it’s about the patient and the people who may benefit from the research.” Although there are still many unanswered questions about the genetic and mechanistic characteristics of RD, there are also several exciting applications in the field. Studying the eye has a unique advantage for developing therapies because it is accessible and immune privileged.5 This means that experiments and tests can be conducted on it without affecting other parts of the body.
One promising area is gene therapy, where healthy genes are transplanted into cells to replace defective genes. The first gene replacement therapy trial for retinal degeneration was successfully completed and the product has been approved by the FDA.6 Specifically, RPE65-associated Leber’s congenital amaurosis was treated by means of subretinal delivery of recombinant adeno-associated virus (rAAV2) vectors carrying the human RPE65 complementary DNA. The treatment improved visual sensitivity for one to three years. However, after this time visual sensitivity declined.6 Future research should focus on improving the longevity of these therapeutic effects.
With the rapidly evolving era of precision medicine—there may be a future in which many of the genetic causes of inherited retinal diseases have been identified. Importantly, the molecular mechanisms underlying disease progression will also be better defined, making it possible
to develop potential therapeutic interventions—such as targeted therapy aimed at slowing down the degenerative process. Factors such as the age of the patient, stage of disease, type of mutation, and patient reported outcome measures will be taken into consideration when establishing future personalized gene and stem cell therapies.
Dr. Elise Héon left us with some words of wisdom: “For young women and men pursuing careers in medicine and/or research: stand tall and do your job, live with integrity—even in times of adversity, and acknowledge that you have strengths and share them with others. Do not be opposed to acknowledging your weaknesses; instead, seek out the necessary resources to help manage them. Take pride in your vulnerabilities which make you who you are; recognize that it is never really just about you—appreciate your supportive environment. Find a mentor to refer to for advice and guidance. Do not refrain from speaking up, and never tolerate disrespectful interactions—do not let that negative energy get to you! Finally, do what you enjoy so that you smile in the morning and feel proud at night.”
- Wright, F. A. et al. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nature Reviews 11, 273-284, doi:10.1038/nrg2717 (2010).
- Nishiguchi, K. M. et al. Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc Natl Acad Sci U S A 110, 16139-16144, doi:1308243110[pii]10.1073/pnas.1308243110 (2013).
- Guo, Y. et al. Advantage of Whole Exome Sequencing over Allele-specific and Targeted Segment Sequencing, in Detection of Novel TULP1 Mutation in Leber Congenital Amaurosis. Ophthalmic Genet, doi:10.3109/13816810.2014.886269 (2015).
- Small, K. W. et al. North Carolina Macular Dystrophy is caused by dysregulation of the retinal transcription factor PRDM13. Ophthalmology 123(1), 9-18, doi:10.1016/j.ophtha.2015.10.006 (2016).
- Zhou, R. and Caspi R. R. Ocular immune privilege. F1000 Biol Rep, doi:10.3410/B2-3 (2010).
- Wright, A. F. Long term effects of retinal gene therapy in childhood blindness. N engl J Med, doi: 10.1056/NEJMe1503419 (2015).