Speaker: Dr. Thomas A. Ciulla
Gene therapy holds promise as a transformative approach in the treatment of age-related macular degeneration. It offers potential advantages of reduced treatment frequency and enhanced safety. Advancements in gene therapy hold promise for improving patient outcomes and providing new treatments of diabetic eye diseases.
Dr. Thomas Ciulla graduated with high honors from Harvard College and earned his medical degree from the University of California. He completed his residency at Harvard Medical School and then a fellowship at Tufts Medical School, where he received the prestigious Heed Fellowship. Before joining the Midwest Eye Institute here in Carmel, Dr. Ciulla served on the faculty of the Indiana University School of Medicine.
A nationally recognized expert in diseases of the eye, Dr. Ciulla has:
- participated in more than 100 clinical trials,
- served on numerous advisory and editorial boards,
- edited medical textbooks,
- presented at more than 200 conferences, and
- authored over 130 peer-reviewed scientific papers.
Sponsored by John Prentice
Program: Research in gene therapy for age-related macular degeneration
Speaker: Thomas A. Ciulla, MD, Ophthalmology, Midwest Eye Institute, Carmel
Introduced By: John Prentice
Attendance: NESC: 111; Zoom: 27
Logged Guests: Debra and Raymond Gravelle, Ed Holt, Patty Matkovic, Margie Sharples
Scribe: Terry Ihnat
Editor: Carl Warner
Talk’s Zoom recording found at: https://www.scientechclubvideos.org/zoom/07272026.mp4
The retina lines the inside of the eye with rods for black and white vision and cones for color vision. There were slides demonstrating a cross section of the eye showing the neural retina, and the retinal layers and pigment epithelium. The pigment epithelium is important for supplying oxygen and removing waste products from the retina in support of the photoreceptors, and it is the area affected with retinal age-related macular degeneration leading to central vision loss and symptoms like metamorphopsia, the so called wavy vision.
Early on there may be no symptoms, but as time goes on one would notice distortion of straight lines followed by a decrease in intensity and brightness of colors, a later loss of central vision, of gradual or sudden onset, with dark blurry areas in the central vision. Night vision can be affected early on.
Two advanced forms of macular degeneration, or geographic atrophy or dry AMD associated with degeneration and death of pigment cells, are visible as white spots in the retina .The impact would be a central blind spot with the slower but progressive vision loss of 2 to 3 lines over 3 years. The pathophysiology is dysfunction of the complement system with the accumulation of drusen which are waste deposits.
In wet AMD, as abnormal leaky blood vessels in the retina cause bleeding and scarring, the visual impact is rapid central vision loss and fibrotic scarring leading to legal blindness. It is due to an overexpression of Vascular Endothelial Growth Factor A, or VEGFA, causing pathological blood vessel growth. Current treatments focus on inhibition of the VEGF. This is accomplished by injections into the eye, but these have to be repeated frequently. This repeat treatment frequency can cause difficulties due to scheduling large numbers of patients requiring it, transportation issues, etc. The number of injections correlates with visual acuity.
It is apparent that a new type of therapy would be helpful, and this would be gene therapy where you can make cells to make their own treatment and not have to have repeated applications. The eye is a perfect organ for gene therapy. There is no immune surveillance in the eye, thus the eye will not reject foreign substances like the genes attached to viruses injected under the retina. Since the cells treated are non-dividing, they will produce the therapeutic gene forever. The procedure is called a pars plana vitrectomy; some vitreous fluid is removed and the injection is performed through needle sized incisions.
There is a form of congenital blindness that has been successfully treated with this gene therapy restoring functional vision to allow for ambulation, light sensitivity, and better visual fields with a good safety profile. This can be done starting at age three.
There are wet AMD gene therapy trials ongoing with the aim of producing anti-VEGF proteins inside the eye reducing the need for repeated injections. Geographic atrophy gene therapies are in an earlier stage targeting complement system modulations combined with neuroprotection by two synergistic proteins. A challenge to the gene therapy is cost.
Other forms of therapy are vitamins for ocular health, which can be helpful but need to be started early. Also, light delivery systems whose aim is to slow AMD by activating mitochondrial function, but not for advanced AMD forms.
In summary, current therapy slows progression but requires repeated injections with limited real world success; gene therapy offers a potential one-time durable treatment turning retinal cells into continuous producers of therapeutic proteins. The eye’s immune privilege and accessibility make it an ideal target for gene therapy. In Luxturna’s success with inherited blindness, we see gene therapy’s transformative potential.
Thomas Ciulla
