Ethical questions about genetic disease and genetic research have been much on my mind since I heard a provocative talk on Citizen Bioscience in the Age of New Media, presented by Marina Levina, at MiT7. The protection of human subjects in research is one of my longstanding professional and scholarly interests. It also holds a deeper, personal significance for me. I have a genetic eye disorder called Stargardt disease.
I’ve written about my own complex ethical debate in deciding whether or not to join a research study in the 1990s that sought to identify a Stargardt gene (see the essay Not This Pig). I ultimately decided not to join that study because the informed consent process was not made accessible to me. That was a serious limitation in a study involving people who were legally blind. Intellectual curiosity led me to the study initially, but I had reservations about it that took a long time to understand. I wrote in 2003:
Hoping for an experimental cure for my eye disease… is not even a blip on my sonar screen. A geneticist who has heard my stories asked me once about this difference in attitudes. The simplest answer is this: unlike heart disease in both its acute and chronic dimensions, I do not experience vision loss as a disease. It is a different way of perceiving the world, and it is rich with its own sensory skills and sweet satisfactions. I think of myself as socially blind; the deficits associated with my blindness result more from society’s limitations than from a disease process active in my body. Read more
Now, after four decades of living with Stargardt disease, there is the possibility of an experimental treatment. Phase I/IIa clinical trials, which are designed to test safety rather than efficacy, are scheduled to begin sometime this summer. They involve gene therapy using a viral vector. I won’t be rushing to join those studies, but I plan to follow their progress.
I should note here that the scientist whom I called Dr. X in Not This Pig is NOT the investigator featured in this news release from Columbia University Medical Center:
The path from basic research to clinical trials is long and arduous?and most new treatment ideas never make it out of the laboratory. This is especially true with gene therapy, which is still in its early stages. One of the few gene therapy treatments to make it to clinical trials is for Stargardt disease, an inherited form of early-onset macular dystrophy that affects approximately 1 in 10,000.The gene for Stargardt was discovered in 1997 by Columbia geneticist Rando Allikmets, and Phase I/IIa clinical trials are scheduled to begin in summer 2011. The hope is that if and when the treatment comes to market, a single dose will restore at least some vision long term, or even permanently.
Allikmets took a circuitous scientific path to the genetics of Stargardt and other eye disorders. Born in Estonia, he spent his childhood studying birds and thought he wanted to become an ornithologist. In college, he decided that molecular biology had more career possibilities. His PhD research at the Institute of Bioorganic Chemistry in Moscow involved building human genome libraries of various organisms and cloning various genes.
In 1991 Allikmets moved to the National Cancer Institute, in Maryland, where he cloned genes of ABC transporters, which are proteins that help transport various molecules across cell membranes. While cloning the ABC transporters, he discovered more than 30 new ones, including one called ABCR. In 1997, he found that ABCR?now called ABCA4?was responsible for Stargardt disease.
Allikmets admits that the road to pinpointing ABCA4 as the cause of Stargardt was simpler than usual. “We were lucky,” he said. “When we mapped the gene, we realized that it was in a region on human chromosome 1 that Baylor College of Medicine researchers had already defined as harboring the Stargardt gene. At that time, scientists could study a region for years without finding the disease-causing gene.”
The discovery spurred Allikmets to concentrate on eye genetics. In 1999, he moved to Columbia, where today he heads the Laboratory of Molecular Genetics in CUMC’s Department of Ophthalmology and is director of research at the Edward S. Harkness Eye Institute.
When Foundation Fighting Blindness (FFB) invited Allikmets to search for a gene therapy treatment for Stargardt, he resisted, citing his lack of experience in gene therapy. But the foundation was persuasive. Allikmets asked Columbia ophthalmology colleagues Peter Gouras and Janet Sparrow to join him, in particular because of their experience with mouse models and with cell biology. The researchers then asked the biopharmaceutical company Oxford BioMedica to work with them. The Columbia team had been using an HIV-based lentiviral gene-delivery system, while Oxford BioMedica was able to provide them with an equine infectious anemia virus (EIAV)-based one, which was more efficient and less of a safety concern. (Lentiviruses are a subset of retroviruses.)
Allikmets and his team also had to go up against the common knowledge that lentiviruses would be inefficient at targeting the eye’s photoreceptors. Although this was the case with mice, they worked superbly with monkeys?which makes sense, as the monkey eye, like the human eye and unlike the mouse eye, has a macula in the center of the retina.
In 2008, Allikmets, Gouras, Sparrow, and other Columbia colleagues, together with Oxford BioMedica, coauthored a Gene Therapy paper on the successful treatment of Stargardt disease in a mouse model, using an EIAV-based vector to add a normal ABCA4 gene to the eye. The paper offered the “proof of principle,” showing that the treatment idea was workable.
Oxford BioMedica completed the required biodistribution studies, which track the distribution of the virus to tissues other than the treatment target, as well as safety studies for the treatment, called StarGen. In March 2011, the company received FDA approval to proceed to Phase I/IIa clinical trials. These trials will study three dose levels for safety, tolerability, and biological activity. If they are successful, the next step will be Phase IIb trials, to test effectiveness of the treatment. Larger, multicenter Phase III trials will further determine efficacy. Fourteen years after Allikmets discovered the gene for Stargardt disease, Stephen Rose, Ph.D., chief research officer for FFB, commended his perseverance in working to advance his early-stage research from lab to clinic.
I couldn’t find a citation yet for the proposed studies on ClinicalTrials.gov, which currently lists seven clinical studies for Stargardt disease.
According to the Wikipedia entry on gene therapy:
On 1 May 2023 Moorfields Eye Hospital and University College London‘s Institute of Ophthalmology announced the world’s first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male, Robert Johnson, in early 2007. Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of the Moorfields/UCL trial were published in New England Journal of Medicine in April 2008. They researched the safety of the subretinal delivery of recombinant adeno associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects.