Q&A: Gene therapy pioneer reflects on career, goals of Opus Genetics

Jean Bennett, MD, PhD, inventor and co-developer of Luxturna, the first FDA-approved gene therapy, now serves as scientific co-founder and sits on the board of Opus Genetics, founded to investigate gene therapies for rare retinal diseases.

Bennett is aiming to use gene therapies to treat ultra-rare diseases with the goal of eventually targeting diseases with more prevalence in the population.

Healio/OSN spoke with Bennett about her career investigating gene therapies and what she sees for the future of Opus Genetics.

Healio/OSN: How did you get started investigating gene therapies?

Bennett: I became interested long before gene therapy had actually been tested in an approved clinical trial. When I was doing my training right after my PhD, it was an exciting time in that technology was beginning to be developed to be able to isolate genes and move them around, to clone them and to be able to express them in cells and ultimately in animals. So, it was natural that I and many other people had a light bulb go off, saying, “Aha! If you can move these genes around, maybe you can move them around to treat disease.” That had not been shown to have been possible to deliver genes to the cells of a living animal at that time. There were a lot of hurdles to cross, including ways to deliver genes safely to the target cells, to be able to measure whether they are active, whether they are making an effect and so forth.

That was some 40 years ago, and when I got my first job at University of Pennsylvania, that is when I started in earnest trying to tackle those various obstacles with my collaborators.

Healio/OSN: How did your path take you from conducting research and inventing Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics) to where you are now, co-founding and sitting on the board of Opus Genetics?

Bennett: Much of my work has revolved around the eye and, in particular, the retina. From my earliest days, I was trying to figure out ways of delivering genes to the retina in living animals with the goal that ultimately that could be used to treat blindness.

We had our first major success around 2000 when we applied what we had figured out on how to deliver genes to the retina. We had cloned them, and we had developed the recombinant viral vectors, which we used to deliver these genes, and showed that they were safe in animals. My collaborators had three dogs born with a congenital blindness that was similar to Leber congenital amaurosis in children. We had isolated the normal version of the gene that, when mutated, caused this disease in the puppies. We decided, “Let’s try this out in these three animals,” and lo and behold, there were dramatic improvements in vision in these puppies. It was so exciting to see these blind dogs seeing, and of course, the natural question was, “Wouldn’t it be great to see blind children see?”

That led to various phases of clinical trials by our group, and there were a couple of others that were contemporaneous doing clinical trials for the same disease. We ended up going all the way through the various clinical trial phases and then getting FDA approval for Luxturna in 2017. We developed the pathway for a gene therapy for blindness as there was no pathway beforehand. We had to develop this on our own using guidance from the FDA. It is natural now to say, “How can we use our experience to develop treatments for other blinding diseases?”

Healio/OSN: Can you break down the goal of Opus Genetics?

Bennett: If I had to put it in a nutshell, it would be to develop a streamlined way of developing interventions for genetic blindness. To further expand, we are selecting some of the most neglected forms of inherited blindness that big pharma traditionally would not touch because they are ultra-orphan (extraordinarily rare), while creating novel orphan manufacturing scale and efficiencies. We aim to carry out these studies, hopefully helping people with Leber congenital amaurosis 5, but also in the process to derisk this sort of approach so that we can treat many other people with primary photoreceptor diseases.

Healio/OSN: Can you explain the importance of investigating therapies for these rare but devastating diseases?

Bennett: These are devastating diseases, and we want to help the patients and their families, who suffer going through a normal day. Helping the families is a major goal; however, we also want to be able to use this experience to develop therapies more quickly for additional blinding diseases. The diseases we are aiming to target are some of the most severe in that they affect babies and young children. There are many other forms of blindness that are not as severe but do rob people of their vision. Perhaps even worse, they rob them of their vision after they have enjoyed vision and become dependent on it, so it is also psychologically damaging. I am thinking in particular of retinitis pigmentosa. If we can show that we can attack the problem in one of the most severe diseases, I think it will help pave the way to attack blindness caused in much more prevalent conditions such as retinitis pigmentosa.

Healio/OSN: There are two currently announced therapies in development set to enter the clinic. Can you go into a little bit of detail as to how these work?

Bennett: Like the target we worked on initially, these diseases all have the common denominator in that mutations prevent production and/or appropriate function of the protein encoded by the gene. So, there is a missing protein or a malfunctioning protein that causes the disease. We are using the simplest approach of gene therapy in that we are delivering a normal copy of the disease-causing gene with hopes of replacing the missing function. There are more complicated approaches of gene therapy, some of which are being addressed by other groups right now, for example, gene editing, in which the goal is to go in and splice in the correct DNA sequence in a specific location. We have selected our disease targets because it is clear that the lack of function of that particular gene or protein is the cause. We believe it is a logical fix.

Healio/OSN: What are the next steps for your research?

Bennett: I continue to try to develop a pipeline that will allow us to move forward and derisk other strategies for gene therapies in a stepwise fashion. We are thinking about metabolic diseases that affect the retina and how we could intervene with those and also strategies that could be generic, where we do not have to deliver a specific gene for each disease. For example, maybe there is one gene that controls a metabolic pathway that could ameliorate the disease in a multitude of conditions caused by different genes.

Healio/OSN: What are the next steps for Opus Genetics?

Bennett: Now that Opus Genetics is formed, the real work begins. We will build a team and develop timelines to move efficiently and safely to initiate our clinical trials and run them swiftly, and carry out natural history studies in complementary fashion to support potential future regulatory submissions. We are basically assembling all those parts and having them work together.

Healio/OSN: Do you have anything else to add?

Bennett: I am grateful to the Foundation Fighting Blindness, the RD Fund, and the funders and partners of this new company for making this possible. Opus is the first spin-out company internally conceived and launched by the RD Fund, and led by industry and business experts Dr. Ben Yerxa, Dr. Rusty Kelley, Peter Ginsberg and Jason Menzo to further the foundation’s mission. They are going out on a limb to try to fuel development of therapies for these rare conditions, and it is a novel approach built by and for patients. I think that they should be accredited pioneers in this space for moving forward the throttle to develop treatments for these devastating conditions.