Federico Mingozzi, PhD,
Federico Mingozzi
Chief Scientific Officer
Spark Therapeutics

The Chief Scientific Officer of Spark Therapeutics, Federico Mingozzi, surveys the hopes and challenges facing the human gene therapy community.

After a distinguished career in academic medicine, including stints at the Children’s Hospital of Philadelphia, INSERM and Genethon in France, Federico Mingozzi joined Spark Therapeutics three years ago as chief scientific officer.

Mingozzi aims to build on the company’s landmark success with Luxturna, the approved therapy for certain retinal diseases such as the type 2 version of Leber’s congenital amaurosis (LCA). In this recent interview with Kevin Davies, Mingozzi discusses his career highlights and surveys the hopes and challenges facing the human gene therapy community. (The text has been lightly edited for length and clarity.)

GEN Edge: Did you always want to be a gene therapist, or was there a “spark” when you decided that you had to move into this field?

Dr. Federico Mingozzi: I started early, when gene therapy was not that popular! My love for everything that is molecular biology and recombinant DNA technology started quite early. I studied biology in Italy at the University of Ferrara, and my PhD mentor, Professor Francesco Bernardi, was the person who introduced me to lab research.

Francesco made the link with Katherine High, and that is how I got involved with gene therapy. That was back—I am going to date myself—in 2000, when I moved from Italy to the Children’s Hospital of Philadelphia (CHOP) for a postdoc. I started working on liver gene therapy, adeno-associated virus vectors (AAV), and immunology. That was the thread of my career for the next 20 years—immunology and gene therapy.

I joined the laboratory of Roland Herzog, who is now professor at the University of Indiana. We worked together in defining the mechanisms responsible for the induction of immunological tolerance with gene transfer with AAV. Then I started working directly with Kathy High, and got involved in the early studies of hemophilia gene therapy and also the early work in ocular gene transfer in collaboration with Jean Bennett at the University of Pennsylvania—the work that today is Luxturna.

GEN Edge: When you first got into gene therapy, AAVs had all the appearances of becoming an important class of vector, correct?

Mingozzi: Yes and no, meaning that I started in gene therapy in probably the dark years of gene therapy, when the field was emerging from a number of important setbacks. There were problems with the early adenoviral platform and the tragic death of Jesse Gelsinger. There were all the issues that emerged with the AAV platform and immunogenicity in the early hemophilia trials. There were also issues in the ex vivo field, with the leukemia in the X-linked severe combined immunodeficiency trial and other trials.

That is when I entered gene therapy, which was the moment when academia really picked up the work. There were a number of companies back in the late ’90s/early 2000s, working in gene therapy, and today they are pretty much all gone, right? So when I entered gene therapy, there was no industry interest in this therapeutic modality. But there was investment from academic centers to try to address the limitations of the technologies and then bring it to patients. It was great, because I think without that the field would not exist as it is today.

The opportunity after my postdoc to join Kathy’s team was great because, at the time, the CEO of CHOP, Steven Altschuler, and CHOP decided to invest in the Center for Cellular and Molecular Therapeutics, a translational medicine center, to bring gene medicine from bench to the bedside.

That was, for a biologist, the wildest dream becoming true, bringing a therapy to patients. There are moments I will never forget the excitement of those days, for example, when we enrolled the first participant in the phase I trial of gene therapy for RPE65 deficiency. It was amazing!

The work that we did in hemophilia was more challenging, but perhaps the most important work I have done in terms of contributing to the understanding of the immune responses to AAV vectors in humans. When we initially approached gene therapy trials, we thought viral vectors were not immunogenic, but then we understood better what was happening, and that allowed for significant progress.

One example of the progress made was the hemophilia B trial led by Amit Nathwani and Andy Davidoff, who were able to modulate the immunogenicity of AAV vectors with corticosteroids, and then they were able to show that that gene therapy can potentially deliver a cure for a disease. We showed that also with RPE65 with Luxturna in the early days. I think these early successes were really the pivotal moment when the investors and the industry started to say, “Wow, there is something there. The technology can really deliver something that is transformational.”

There was also important progress made in other fields of gene therapy, including the work of the colleagues at the San Raffaele Hospital in Milan, Italy, on the ex vivo gene transfer platform, French and U.S. teams as well, in evolving the lentiviral vector platform to become safer. It was a nice parallel of in vivo and ex vivo gene therapy, and then clinical success started to become more real.

GEN Edge: How has the gene therapy field been able to recover from those setbacks? What were some of the biggest issues that the field as a whole has had to really work on and understand better to where we are today?

Mingozzi: I think a bit of everything. I will put it in two main categories. One is the platform, the other is understanding the biology. We started to have better gene delivery tools—there was the first-generation AAV, then more efficient AAV vectors came to fruition, to be used in the clinic. The same for ex vivo, the first platform was based on gamma-retroviral vectors, and then the next generation of retroviral vectors came along, which was a more amenable platform for clinical translation.

Then the biology piece—better understanding the immunogenicity of the vectors we use for gene therapy for in vivo, and for ex vivo—as you can imagine, a more in-depth understanding of the drivers of the risk associated with gene integration.

GEN Edge: What proportion of trials does AAV make up?

Mingozzi: It is a big proportion of the trials. The flavors of AAV that are now reaching the clinic span a broader range than in the past, starting from natural serotypes, which were of course the first ones adopted, to a growing number of engineered serotypes. The appetite for new serotypes is nearly infinite, and, if you look at the landscape, both in academia and in industry, you find more and more groups and companies working on engineering new AAV serotypes.

GEN Edge: What was the genesis of your decision to take a break from academia and join Spark Therapeutics about 3 years ago?

Mingozzi: The funny thing is that I left CHOP before Spark Therapeutics was funded, and I went to France to work for the French Muscular Dystrophy Association and Généthon. It was really a fantastic journey in gene therapy, and I think it was fantastic. A little more than 3 years ago, I started talking to Spark Therapeutics about one of the programs that was developed in my laboratory—a gene therapy for Pompe disease, which is now in the Spark Therapeutics pipeline. Finally, I was offered the position of chief scientific officer, which was a really humbling moment for me.

These days, if you work on gene therapy it is likely that you receive many offers for jobs in the industry every week. However in the case of Spark Therapeutics, there was an emotional attachment to the programs, but also the recognition that it was a great company with great science and a fantastic culture. So I decided to join the company. I was happy in France and had a tenured position with INSERM. It was a difficult decision, but at the end I decided to move back to Philadelphia and join Spark Therapeutics.

GEN Edge: Spark is best known for historic success with Luxturna. How has that drug fared since its approval? And how has the company benefitted from that experience? How does that experience provide momentum for the other clinical programs that are now coming through the pipeline?

Mingozzi: It is a great question. First of all, I feel lucky that I have been involved with Luxturna from early on. When I joined Spark Therapeutics is about when the drug was approved by the FDA.

There are many learnings. The first one is that gene therapy is a therapeutic modality that can go all the way to become a drug—importantly, all the regulatory hurdles can be overcome. That is very important for the field, and also to drive the interest of industry in the specific technology.

There are additional learnings related to doing gene therapy in the eye. We know more that, for example, the route of administration to the eye can present important complexities, and so as we think about larger indications, we need to consider that carefully.

Every time I hear about Luxturna, I am happy, because it is a very positive and successful story. It is a drug that is really changing the life of patients, and this is what matters the most. There are also additional learnings. Luxturna is a treatment for an ultrarare disease. There was no molecular diagnostics, for the most part, for retinal disease associated with biallelic mutations in the RPE65 gene. That means that, for example, we had to identify the eligible patient population, and the actual commercial development was complicated and brought a lot of learnings for Spark Therapeutics and required a lot of innovation.

GEN Edge: Luxturna is injected subretinally. There is a lot of work in developing new, evolved AAV vectors that could in principle provide a less invasive injection that might deliver the same therapeutic benefit. Would Spark Therapeutics employ this approach, if not for a new and improved version of Luxturna, maybe for other blindness conditions?

Mingozzi: Certainly, for example, there is a lot of interest around using AAV capsids that can transduce the retina through direct intravitreal injection in the eye. Then essentially you are simplifying the administration procedure. You do not need the operating room, you can do it theoretically in the outpatient setting.

At the moment, there are a couple of trials wherein this paradigm is being tested. The jury is still out. Definitely there is interest also on our end, how to improve the delivery to the eye. Of course, as we think about bigger indications, it would be very hard to serve large patient populations when your administration procedure is very cumbersome, it requires a lot of operating room time.

GEN Edge: As Spark Therapeutics’s chief science officer, how does the pipeline look to you? What are you most excited about that we will be hopefully seeing moving toward approval in the coming months and years?

Mingozzi: I am excited about each and every asset in our pipeline. And I am also excited about the lines that we are not going to tell you about!

The emphasis and engagement of Spark Therapeutics in hemophilia remain very very important. Hemophilia B is now in phase III with Pfizer, and for hemopnilia A, the program is advancing well. We recently presented at the International Society of Thrombosis and Hemostasis, where we showed very important evidence of durability in the patients enrolled to date. So that is very exciting.

I am also excited about what is coming up next in the liver. We have an open trial for Pompe disease. We have ocular programs that are advancing well, and last, but not least, there is the central nervous system—we have Huntington and other programs wherein I think there is a lot of interest, and a huge unmet medical need. Gene therapy there has also the potential to deliver transformational results.

GEN Edge: What is your approach in Huntington’s disease, which is of course a dominantly inherited disorder?

Mingozzi: The approach is a silencing approach, the idea is to knock down the expression of the Huntingtin (HTT) gene. It is similar to other approaches of gene therapy that are in development. It is not allele specific. The idea is that as long as you knock down the mutant HTT allele sufficiently, and it does not matter whether you knock down also the allele that is not detrimental, then you would have a therapeutic impact.

GEN Edge: There have been three reported fatalities in an AAV trial that happened earlier this year. What has been your reaction, or perhaps the reaction of your peers, to this news? Is this a wake-up call for the gene therapy field as a whole?

Mingozzi: Definitely the field is watching closely. It is too early to know exactly what happened. I think clearly it is an unfortunate chain of events, and based on what it takes to bring our gene therapy to the clinic, the assumption is that this was not predicted in preclinical studies.

Now what we need to do is to understand what happened. The myotubular myopathy results in the gene therapy trial are quite impressive in terms of what can be done for this disease, which does not currently have a treatment. Now we need to understand what happened, and then move forward.

This is a very specific situation wherein very high doses of vector were used. I do not think we have the same safety concern when lower doses of vector are used. But to tackle certain diseases, we need more vector infused, and we will have to do our best in the field, to understand what the drivers of the observed toxicities are.

GEN Edge: Are you interested in nonviral delivery methods? Are you seeing promising data using nanoparticles or liposomes that might solve some of these immunogenicity problems?

Mingozzi: I will say clearly Spark Therapeutics is interested in gene transfer as a whole, and we are keeping ourselves up to speed with all the technologies, including nonviral (delivery). There is a saying: mice lie and monkeys do not tell the truth… Until we have got clinical data, it will be hard to decide whether these technologies are really up to the promise. I think it is exciting, potentially.

GEN Edge: Would you consider using CRISPR or genome editing for a particular therapeutic indication if traditional gene therapy or gene silencing could not work? Or is genome editing really the specialized arena for companies that are set up to do gene editing? Do you feel you can use genome editing down the road if the situation calls for it?

Mingozzi: What we are seeing is that all lines are blurred, because the lentiviral vectors are primarily being used ex vivo, and now there are initiatives to use them in vivo. AAV vectors are a platform for in vivo. And AAVs are used as a donor template for ex vivo in gene editing, right? So the line is not clear cut. Gene editing is relying on some delivery platform. You need to deliver the gene editing tools in one way or the other.

I think gene editing has many applications and huge potential, and ex vivo gene editing is already in the clinic. Ex vivo is the ideal setting, because you modify a cell, and you do it often times in a physiological way by correcting a gene defect. And then you implant it back, and you even overcome potential issues with immunogenicity of these gene editing tools.

For in vivo gene editing, I think there is promising data, and potential applications, and there is even nuclease-free gene editing, that has been proposed, based on technologies based on AAV that integrate in the genome. Again, things will have to be tested in the clinic to see how safe and efficent they are.

But then there are definitely areas where they could be very useful. Let us think about gene editing in a developing liver, where AAV would not have long-term expression. Then gene editing could be the way. The alternative would be to be able to readminister AAV.

GEN Edge: Spark Therapeutics’s founder Kathy High has now retired. How are you and the rest of the Spark Therapeutics team going to fill her shoes?

Mingozzi: First of all, I do not think Kathy will ever retire. She is too smart and has too much energy. You are right, she left a big void, we are doing our best to fill the void! Spark Therapeutics has many very smart people, very engaged and motivated people.

We are recruiting amazing people. We just recruited a new Chief Medical Officer, Dr. Gallia Levy, who joined Spark Therapeutics from Genentech, which like Spark Therapeutics is a member of the Roche group. It is a new exciting era for the company. Kathy represents the legacy of Spark Therapeutics, and we are very excited about the future ahead of us.


Human Gene Therapy, published by Mary Ann Liebert, Inc., is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. The above article was first published in the October 2020 issue of Human Gene Therapy with the title “The Italian Job: An Interview with Federico Mingozzi”. The views expressed here are those of the authors and are not necessarily those of Human Gene Therapy, Mary Ann Liebert, Inc., publishers, or their affiliates. No endorsement of any entity or technology is implied.

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