RETINA CONVERSATIONS: A Historical Perspective on Gene Therapy for Retinal Disease

A discussion with Mark Pennesi, MD, PhD.


When Mark Pennesi, MD, PhD, was a bioengineering undergraduate student at the University of Pennsylvania, he needed a summer job and landed a position at the Retina Foundation of the Southwest where David Birch, PhD, was conducting research on retinitis pigmentosa, one of the most prevalent and debilitating inherited retinal diseases (IRDs). Though he knew nothing about IRDs at the time, the young student was almost immediately intrigued by the research and made an early career choice. He decided that he wanted to play an important role in the efforts to combat retinitis pigmentosa and other IRDs.

After completing a combined MD/PhD program at the Baylor College of Medicine, Dr. Pennesi went on to an ophthalmology residency at the University of California, San Francisco. During residency, he was awarded the Hogan/Garcia award for the best resident research project. After residency, he completed an ophthalmic genetics fellowship under the tutelage of Richard G. Weleber, MD, at Casey Eye Institute in Portland, Oregon.

Dr. Pennesi has quickly moved to the top ranks of retina specialists focusing on IRDs and today is an associate professor in ophthalmology and chief of the Ophthalmic Genetics Division at the Casey Eye Institute of Oregon Health & Sciences University. The Casey Eye Institute’s gene therapy program is world renowned, with leading experts currently overseeing numerous gene-therapy clinical trials. Patients travel from all over the world to participate in these groundbreaking studies targeting severe inherited blinding disorders.

Dr. Pennesi was also named study chair of the recently announced Pro-EYS study, a natural history study for people with retinitis pigmentosa caused by mutations in the EYS gene. The goals of the international, 4-year study include estimating the rate of disease progression and evaluating the usefulness of various outcome measures for future clinical trials for emerging therapies.

Retinal Physician was able to sit down with Dr. Pennesi recently and review the past, present, and potential future for gene therapy in combating inherited and other retinal diseases.

Mark Pennesi, MD, PhD

Q. When researchers began to look at the possibility of combating genetically based diseases through gene therapy, why were IRDs a good initial target?

A. The eye is an ideal place to do gene therapy. We have 2 eyes, and most IRDs are symmetrical, allowing one to compare a treated eye with an untreated eye. The subretinal space demonstrates immune privilege relative to other parts of the body. Most inherited retinal diseases are characterized by the loss of function of a single gene, making them easier to fix than complex inherited diseases such as glaucoma or age-related macular degeneration. Also, there was a rich history of developing preclinical animal models which formed a foundation for testing these novel therapies.

Q. Which institutions were in the vanguard of gene therapy for retina?

A. I hesitate to be too specific because there are so many people who deserve credit, but if you look at the 3 simultaneous papers published in 2008 for the first RPE65 gene therapy trials, you can see that much of the early work was done at University of Pennsylvania in Philadelphia, University College of London, Cornell University in Ithaca, New York, and the University of Florida in Gainesville.1-3

Q. We know that the progress of gene therapy in general has not always been smooth. Can you identify any obstacles or events that set back the research effort for gene therapy overall and that also affected research for gene therapy in retina?

A. The death of a healthy subject in one of the early clinical research programs utilizing gene therapy for a systemic disease4 put gene therapy overall under a cloud for years. The pioneers of retinal gene therapy were subjected to heavy oversight to ensure that similar adverse events didn’t happen again. Fortunately, their persistence paid off, and now we know that gene therapy can be safely delivered with a positive effect.

Q. How do you regard the importance of the groundbreaking research with Briard puppies that proved the effectiveness of gene therapy for inherited retinal disease in canines?

A. It was very important. Rodents lack a central concentration of cone photoreceptors and have very small eyes. Having a natural occurring model of RPE65-related retinopathy in a large animal not only allowed testing for the safety and efficacy of the vector, but also provided the ability to develop the surgical techniques that would later be used in human trials for voretigene neparvovec-rzyl, the first FDA-approved gene therapy for a genetic disease.

Q. How did the use of the Briard dog Lancelot5 as sort of a national “spokesdog” for gene therapy in IRD increase interest and funding for pursuing research in this area?

A. There is a famous photo of Lancelot appearing before Congress. Lancelot put a “face” — albeit a canine face — on gene therapy. I think he was quite effective in helping the public understand a complex topic such as gene therapy. These endeavors were also a positive factor for increasing awareness about rare IRDs and attracting increased funding for this area of research.

Q. What is the difference between gene editing and gene replacement? Are there specific IRDs that would lend themselves more to gene editing than to gene replacement? Who are the leaders in this emerging field?

A. I prefer the terms “gene augmentation” or “gene supplementation” rather than gene replacement, as the native mutated gene is not replaced. It is still there, but its loss of function is supplemented by the normal copy of the gene that is added. Gene augmentation is going to be most useful for autosomal recessive diseases where there is a loss of function. In gene editing, we can target a sequence of the native DNA and that causes disease and cut it out, thereby decreasing the toxicity or restoring function to the encoded protein by that gene. Currently, gene editing is being investigated for a subset of mutations, but hopefully it can be used for all mutations. Editas and its partner Allergan seem to be furthest ahead in the development of gene editing in retina and are planning trials for CEP290-related retinopathy.

Q. Much research is currently under way to combat IRDs through gene therapy. Where should we expect to see the next breakthroughs in this area?

A. I think one of the newer and exciting technologies involves using antisense oligonucleotides to modulate messenger RNA signals to restore protein production or silence dominant gain-of-function mutations. ProQR has therapies in various stages of development for several IRDs, including CEP290-related retinopathy and USH2A-related retinopathy. Recently, the first patient was dosed in the phase 1/2 Aurora clinical trial of QR-1123 in patients with autosomal dominant retinitis pigmentosa.

Q. In a related area, both Adverum Biotechnologies and REGENXBIO have ongoing trials using gene-derived anti-VEGF for long-term, continuous treatment of wet AMD. Thus far, the early data have been promising. Do you see this gene-based “biofactory in the eye” approach as having significant potential and being extended to other eye diseases?

A. This is definitely a category of gene therapy. The early results from the Adverum and REGENXBIO clinical trials have been exciting. With these trials, gene therapy is now expanding from rare IRDs to more prevalent retinal diseases like wet AMD. There are still lots of questions, especially about long-term expression of gene-derived therapies.

Q. Though research in gene therapy is progressing well, do you see any significant issues or side effects that still need to be resolved?

A. Though we now know that gene therapy can be effective in retinal disease, we have a long way to go in optimizing expression and combating concerning side effects, such as inflammation. I don’t think that we fully understand the nature of the inflammation that can be seen with gene therapy. We need to better understand what the source of inflammation is, what pathways mediate it, and how best to prevent it. RP


  1. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979-990.
  2. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2231-2239.
  3. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240-2248.
  4. Raper SE, Yudkoff M, Chirmule N, et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther. 2002;13(1):163-175.
  5. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28(1):92-95.

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by REGENXBIO.