Innovation in Retina

AGTC: Gene Replacement For Orphan Retinal Diseases

Innovation in Retina


AGTC: Gene Replacement For Orphan Retinal Diseases

The company is about to begin human clinical trials.


In the mid 1990s, a group of pioneering academic researchers who believed in the future of treating — and possibly even curing — a range of diseases through gene replacement began to coalesce around the newly formed Powell Gene Therapy Center at the University of Florida in Gainesville.

These researchers were focused on one specific gene replacement concept, the use of a safe, benign adeno-associated virus (AAV) as a “delivery truck” to replace a broken gene with a healthy one by way of a single injection. The goal was to provide long-term therapeutic value over many years as the healthy gene began to express on its own to eliminate the disease symptoms caused by the broken gene.

“These were world-class researchers, but they also recognized that they needed help in such areas as business and clinical research so they started a company,” says Sue Washer, MBA, an experienced entrepreneur who was brought in to serve as CEO of the newly formed Applied Genetic Technologies Corporation (AGTC) in 2001. Ms. Washer, one of the first graduates of the entrepreneurship program at the University of Florida, who also has a degree in biochemistry, had previously held technical management positions at Abbott Labs, worked in sales and marketing at Eli Lilly and been involved in several local startups.


“The company initially looked at primarily targeting respiratory diseases, but one of the founders, Dr. William Hauswirth (PhD), of the University of Florida, was involved with a successful collaboration between the University of Pennsylvania, Cornell, and the University of Florida that restored sight to blind Briard dogs that had a canine version of Leber’s congenital amaurosis, ” says Ms. Washer.

“These dogs have defects in the same gene that causes this disease in humans. As we looked at the unmet medical needs in treating rare eye diseases, the importance people place on their sight, and the very good animal research models that were available, we began to recognize the real opportunity in orphan ophthalmology,” she says.


Another encouraging factor was that the FDA grants companies that develop successful treatments for orphan diseases exclusive marketing rights and the potential for “fast-track” status, two major commercial advantages.

Jeffrey Chulay, MD, DTM&H, vice president and chief medical officer, and Sue Washer, AGTC president and CEO, see a bright future for gene replacement in ophthalmology.

Ms. Washer also notes that regulatory agencies currently accept clear and well-recognized endpoints for clinical trials in retinal diseases. These include improvements in visual acuity, visual fields, contrast sensitivity, and color vision.


Once AGTC established that the company should place its primary focus in ophthalmology, the research team reviewed dozens of potential indications. They selected three inherited orphan retinal diseases as initial targets: x-linked retinoschisis (XLRS), achromatopsia (ACHM), and x-linked retinitis pigmentosa (XLRP). AGTC based its selections on proof-of-concept data in animal models, which demonstrated that AAV gene therapy could improve the vision in animals with these diseases. These data suggest that similar success may be possible in treating human disease.

“These three diseases are classified as orphan, but when you combine the numbers in the United States and Europe, each one has 20,000 to 40,000 afflicted patients,” says Ms. Washer.

Because all three of the diseases have a common mechanism — mutations within genes that produce proteins that play key roles in the retina — the success of gene therapy in treating one of the diseases could translate into success in treating all three, she says.


Recently, AGTC has been encouraged by the fact that the company’s AAV gene replacement concept has been successful in targeting and expressing proteins in specific types of retinal cells in primates. This achievement has enabled the company to schedule its first human clinical trials in XLRS and ACHM to begin early next year, with preliminary data available by the middle to end of 2015.

“Success with primates is a major step for us,” says Ms. Washer. “The primate eye is very similar to the human eye, much more so than the eyes of lower mammals used in preclinical testing. Using our AAV delivery system successfully in primates with good safety and specific targeting gives us confidence to move ahead.”


As a professional manager who has established a number of important relationships in the realm of bioscience, Ms. Washer has also played a key role in attracting more than $90 million in venture capital and grant financing over the years. Recently, AGTC (NASDAQ: AGTC) took the major step of offering its shares to the public raising an additional $57 million.

“We felt that going public would give us greater ability to meet our cash needs for later-stage clinical trials and to provide additional flexibility as we add new programs,” says Ms. Washer. “We now have the resources to move forward independently in our lead programs.”


The most prominent potential competitor in the ophthalmology AAV gene therapy space is Avalanche Biotechnologies (Menlo Park, CA), which recently made news by signing a long-term partnership agreement with Regeneron Pharmaceuticals (Tarrytown, NY), the developer of Eylea (aflibercept) an anti-VEGF therapy for treating a range of retinal diseases. However, Avalanche and Regeneron are targeting wet AMD, DME, retinal vein occlusion, and the more prevalent retinal diseases rather than the orphan indications that AGTC is initially pursuing.

“We and Avalanche are working along similar lines, but we can all be successful,” says Ms. Washer. “We see plenty of room for a number of players in this space. Also, while we are currently focused on retinal diseases, we may look at other indications for AAV gene therapy in the future, given the potential of our platform to provide long-term therapeutic value. Currently we have a product for a respiratory indication in phase 2 clinical testing.”

Also, AGTC had a previous relationship with Genzyme, a division of Sanofi, in developing an AAV program for wet AMD, but that partnership has ended, and both companies are now working independently on their own AAV initiatives.


When asked what excites her most about the potential of AAV gene replacement, Ms. Washer says early successes with both the Briard dogs and with humans have demonstrated the long-term therapeutic value of AAV treatment. Sustained expression has been observed for more than 10 years with the dogs, more than four years with humans treated with an AAV-based therapy for Leber’s congenital amaurosis, and two years in humans treated with an AAV-based treatment for the respiratory indication.

“With AAV, you eliminate the patient compliance issues that are frequently associated with chronic disease therapy and greatly improve the quality of life for the individual,” she says. “AAV has been shown to be a safe vehicle for gene delivery in hundreds of patients in dozens of clinical trials across the industry. We believe the science supports a promising future for AAV gene therapy.” RP