Blindness: Genetic discoveries that lead to treatments

A profile of Robert Koenekoop, MD, PhD
By Alison Burch with Robert Koenekoop
Director of Pediatric Ophthalmo-logy at The Children’s, Dr. Robert Koenekoop has always been fascinated by the fact that babies are born with very little vision and then develop normal vision in the first year of life.
“Any interruption of this delicate process leads to blindness,” he says. The research conducted in his Ocular Genetics Laboratory at McGill grew from his wish to make an impact by studying the genes that are important for retinal development and function.
The causes of blindness are most often hereditary, Dr. Koenekoop points out, and currently there are no cures. However, research is revolutionizing the management of Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). In these disease groups, vision is lost because of a genetic insult leading to photoreceptor cell death or cell dysfunction. Dr. Koenekoop’s laboratory is contributing to the discovery of new genes and mechanisms as well as testing new treatments based on these findings.
“I am happy I entered this blossoming field 15 years ago,” Dr. Koenekoop says, “because now we are in a revolution of new ideas, as blindness is in part treatable through gene replacement or drug therapy.”
The curiosity that drives a researcher was a part of Dr. Koenekoop’s early life. Growing up in Holland, he was interested in biology and natural history, as well as in sports. “I collected everything I could find outdoors in streams, oceans and woods, and I played a lot of soccer and started jogging and biking,” as he recalls. These activities led to studies in biology and population biology at the University of Utrecht.
The path to medicine and McGill came after a doctorate in molecular biology from Clark University, Massachusetts. At McGill, Dr. Koenekoop hoped to join a unique group of clinician scientists with the creative freedom to pursue their ideas.
“After I completed my residency in ophthalmology, I could see the potential impact of genetic studies for eye disease, especially visual disorders of the human retina,” Dr. Koenekoop says. At McGill and The Children’s, his work spans both ends of the research spectrum. “In our basic science work,” he explains, “we discover new genes for childhood blindness using a variety of new techniques, and at the other end we are testing new drugs for childhood blindness in those children where we have identified specific gene defects.”
The McGill Ocular Genetics Labo-ratory, with collaborations from the University of Nijmegen in Holland and Baylor in the United States, has discovered the last four of 15 genes identified to date for LCA and two new genes for RP.
One gene discovered by another group, RPE65, was found to be treatable by gene replacement— first in blind mice, then in blind dogs, and recently in humans. More than 30 humans have been treated, including children, and some vision has been restored. This has led to a new drug for blindness that bypasses the genetic block in the retinoid cycle.
Dr. Koenekoop’s laboratory is participating in the first human drug trial for LCA patients with LRAT or RPE65 mutations (QLT, Vancouver). Initial results point to the existence of dormant photoreceptors that can be revived by gene or drug replacement, confirming that genetic discoveries can lead to an understanding of disease pathways, then to treatments.