It’s in the ‘Genes’: The Quest to Develop a Cure for Rare, Genetic Diseases

Innovation That Matters
Arthur Tzianabos

By Hui Cai, VP of Corporate Alliances at WuXi AppTec (@HuiCai2)

We always felt like gene therapy was coming back, and it sure did. This technology represented a great way for us to come together as a team again to deliver the promise of gene editing and therapy in a real novel way.”

Although 95% of rare diseases don’t even have an FDA approved drug treatment, Arthur Tzianabos and his colleagues at Homology Medicines are pioneering a new technology that holds the promise of potentially offering a cure for rare disease.

The company – which recently launched with a $43.5 million Series A from 5AM Ventures, ARCH Venture Partners, Temasek ,and Deerfield Management – is leveraging groundbreaking technology on gene editing and gene therapy vectors derived from naturally occurring human adeno-associated viruses (AAVs). The company plans to harness its platform to rapidly advance a diverse pipeline of new rare disease medicines.

Tzianabos – who has 25 years of experience in the biotechnology industry leading teams in the discovery, development, clinical translation and commercialization of new treatments for rare diseases – is certainly up for the task.

I recently had an inspiring conversation with Tzianabos, who shed some light on Homology Medicines’ novel science and strategy, as well as his drive to help steer the development of the next generation in genetic medicines.

Hui Cai: What attracted you to Homology’s science and team?

Arthur Tzianabos: One of my former colleges from Shire, Albert Seymour, was looking at a CSO role with the company, and another one of them had actually already joined, and that’s our COO Sam Rasty. The technology is unbelievable, and if it can do what it’s supposed to do in terms of gene editing in a very specific way with high efficiency and in a very non-nuclease way, that would be incredible. When we both looked at the technology and the data we were blown away by just the potential power of the technology. We had been together quite a while at Shire and were part of a team that drove the gene therapy strategy and led investments in a number of companies in gene therapy, and this is five or six years ago. We always felt like gene therapy was coming back, and it sure did. This technology represented a great way for us to come together as a team again to deliver the promise of gene therapy in a real novel way.

Hui Cai: Translating science into therapeutics is hardly ever straightforward. Compared to other gene editing technology, what is the advantage of Homology’s science, and how can you make sure it will not get lost in translation?

Arthur Tzianabos: That’s a great question. Translating great science and ideas into meaningful treatments for patients is something that I have been very focused on my entire career, all the way from academia to industry. In looking at this technology, what I saw and what my colleagues saw was the advantage of having the ability to harness a naturally occurring mechanism such as homologous combination in a targeted way with high efficiency to essentially gene edit, and then correct mutations in underlying disease and be able to do this is in a very simplified, single component system without nucleases. This can be done in vivo with the AAV vectors. So the advantages over other gene editing technologies as I see it is you aren’t introducing an exogenous  system, such as a nuclease like  CRISPR/Cas-9 which is a bacterial system and you are trying to get it to adapt to humans. It’s a system that’s very effective at inducing these double-stranded breaks in DNA. What hasn’t been harnessed yet is controlling where these nucleases cut, so you have the risk of introducing off-target mutations and miscellaneous breaks in the DNA that can be filled with any kind of nucleic acid. I see the Homology approach potentially as a more specific, natural mechanism from a naturally occurring AAV vector that can deliver in a much simpler way – there’s no ex vivo component to this – you can do this in vivo. So a single injection with an AAV vector, which has been obviously been used in hundreds of clinical trials now and showing to be safe, is really a huge advantage that I think we have in gene editing.

Hui Cai: What is your strategy for developing the first application?

Arthur Tzianabos: Our strategy is to prove the platform pre clinically. Ultimately, we feel that rare disease is the best platform to begin with. Rare diseases are obviously caused by single mutations, and you can really link disease to DNA, and if you can correct that then you have the ability to potentially offer a cure. For the first time in genetic diseases, you can offer potentially a cure for that disease. So this is very exciting. We, obviously as a team, have a lot of experience developing rare disease therapies. We do feel like as science progresses, more of the larger diseases will ultimately be found to be caused by genetic mutations. For example, in ALS, you have the SOD1 mutation that causes a small percentage of the total number of ALS cases, but you can link that to a certain underlying genetic cause. So, ultimately I think the platform can be broadened out to go after some of these diseases where you know the underlying genetic mutation that causes it.

Hui Cai: So how far will the Series A carry through?

Arthur Tzianabos: With the Series A, our plan is to prove out the technology from a gene therapy and gene editing perspective pre-clinically, and really use that capital to show proof-of-concept pre-clinically for the platform in disease models that we feel are highly translatable to the clinic. So these are disease models that are pretty predictive of whether or not your therapy’s going to work. I think with this team, I would expect us to be moving as fast as we can toward the clinic.

Hui Cai: Is being global and forming partnerships an important part of the company’s development strategy?

Arthur Tzianabos: I think execution is first and foremost our priority. Partnerships could help us expand the platform more quickly, but I think for the time being our primary focus is on the execution of the proof-of-concept and platform. From the perspective of being global, I think in the rare disease space, one of the important things is you can’t just focus on the U.S. for example; you have to focus globally because you need to find patients around the world in order to be successful in launching any kind of rare disease therapeutic. For example, while I was at Shire, we had a product for Fabry disease called Replagal, which was approved in about over 40 countries in order to drive the growth of that product. And that’s true of almost every therapy you see out there for rare disease right now. So there is a global component of this very early on in rare disease.

Hui Cai: So let’s talk a little bit more about rare diseases. According to data I have, there are over 7,000 kinds of rare diseases, and only about 400 FDA approved drugs. This is a huge unmet need. Do you think genomics will be the silver bullet for rare diseases?

Arthur Tzianabos: There is a huge gap in terms of unmet need, and I think genomics will be a big part of it, because the more you understand the underlying cause of these diseases the more effective you will be in developing therapies. I think one of the big gaps is in diagnosis for these diseases. What you’ve seen in the past is usually once a therapy is approved for a certain disease, all of a sudden you see that there are a lot more patients out there than anybody thought because now they know there’s a treatment. I think one of the things that will really aid the development of rare disease drugs is newborn screening as a diagnostic, so that you know early on if your child has a rare disease. Right now, there are relatively few of these that are approved, and it’s a complicated area. But the ability to have the newborn screening for a whole range of these diseases could really reveal a lot more opportunity to do rare disease drug development. I think that’s one of the things companies have tried to do, but today it’s just not very effective.

Hui Cai: What are your key considerations in evaluating a piece of academic science for its commercial potential?

Arthur Tzianabos: I want to be technology agnostic; I don’t want to be married to one type of technology to try to solve a disease. I’m going to take a multiple-strategy approach with different technologies to try to cure, for example, muscular dystrophy, or cystic fibrosis. I don’t think you can really predict how long it will take a certain technology to mature and become a tool for you to try to treat diseases. For example, it took 20-plus years for monoclonal antibodies to go from discovery to an actual therapeutic. You look at RNAi, RNA interference, which has taken close to 20 years and a lot of investment. What I try to do is look at technologies that can be translated in a much shorter time frame. What that means is that it has to have aspects of it that are translatable, developable, and that can withstand all the testing that a drug needs to go through in order to have a very big treatment effect.

Hui Cai: You were Harvard professor. Why did you move to industry?

Arthur Tzianabos: It is really personal. It comes from my father, who was a physician.  I loved what he did in terms of helping people who were very ill. I followed him doing rounds in the hospital, and I had a deep interest in trying to help patients. So when I came to the decision of, am I going to become a doctor or become a scientist, I said, ‘Dad I’m going to be a doctor just like you.’ And he said, ‘Look, I think to help the most patients possible you’re better off becoming a scientist and developing new medicines for patients.’  So he really was a big driving force in me having that commitment. I think it’s because I grew up around a hospital seeing patients suffer and seeing how helpless sometimes my dad felt not having the tools and treatments to save some of his patients. That was further cemented when I came into the rare disease space and met families who had children with rare genetic disorders, and interacted with them.  I saw how these devastating diseases not only affect the kids but the entire family. Families had to basically move to different countries just to get treatment. It’s not just about the patient; it’s about that patient’s entire family.  So for me, it continues to be highly motivating to be able to have the privilege of doing this every day and working with the people here to bring potential cures to patients suffering from rare genetic disorders.

Hui Cai: Thank you Arthur for sharing this personal story. This is very compelling. Do you have other closing thoughts?

Arthur Tzianabos: I really feel that Homology Medicines is at one of the most exciting times in terms of the ability to help offer a cure for patients. We often talk about helping or treating patients, and I think we’ve been limited in our technologies to treat patients, but not cure them. What excites me greatly is having this team and the technology married together to potentially offer cures for these rare genetic disorders. It’s an honor to undertake that every day.

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