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Daniel Eisenman, Paul Gulig, and Adam Soloff Explore The Exponential Rise of Gene Therapy and Unlocking Its Potential Promise

May 26, 2021

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About the Advarra In Conversations With…

The future of healthcare innovation hinges on research and clinical trials. Advarra sits down with leading experts to dig into pressing issues and explore cornerstone solutions. Join us as we discuss topics and trends impacting the healthcare of tomorrow and advancing clinical research to be safer, smarter, faster.

About this Episode:

The Gene Therapy market is accelerating at unprecedented speed, with expected growth globally of 16.6% between 2020-2027, but it hasn’t been an easy road. In this episode, Advarra’s Daniel Eisenman talks with Dr. Adam Soloff and Dr. Paul Gulig for an enriching discussion about the growth, misconceptions, and promise of gene therapy.  

Discussions with:

Daniel Eisenman
Executive Director of Biosafety Services at Advarra

Paul Gulig
IBC Vice Chair at Advarra, Professor in the Department of Molecular Genetics and Microbiology at the University of Florida, IBC Chair at the University of Florida

Adam Soloff
IBC Committee Member and Scientific Reviewer at Advarra, Assistant Professor in the Department of Cardiothoracic Survey at the University of Pittsburgh, Cancer Immunologist at the UPMC Hillman Cancer Center

Episode Transcript:

Daniel Eisenman (00:03): So, hello, this is Dan Eisenman and I’m the Executive Director of Biosafety Services at Advarra. I’m really excited to be joined by Dr. Adam Soloff and Dr. Paul Gulig for the third episode of Advarra In Conversations With. Today, we’re going to delve into the exponential rise of gene therapy, gene therapy’s potential to bring breakthroughs across disease states, and what we need from a regulatory perspective to bring this promise to patients. As part of Biosafety Services, I run the Institutional Biosafety Committee, or IBC, which focuses on review of research involving gene therapy and genetic engineering.

Clinical research professionals are likely familiar with the role of the IRB in terms of assessing risks to human research subjects. The IBC has a slightly different focus; it focuses on assessing the risks involved with engineered genetic material, not just to research subjects, but to the research staff, the community, and the environment around the research site. With that said, let’s turn it to my colleagues, so they can introduce themselves … Paul.

Paul Gulig (01:18): Hi, I’m Paul Gulig I’m an IBC Vice Chair at Advarra, I’m also a professor in the Department of Molecular Genetics and Microbiology at the University of Florida College of Medicine where I’ve been on the faculty for 33 years. I study antibiotic development and also how bacteria cause disease. I’m also the Chair of the University of Florida Institutional Biosafety Committee. With that, I’ll turn it over to Adam.

Adam Soloff (01:44): Hi I’m Adam Soloff, I’m an Advarra IBC Committee Member and Scientific Reviewer. I’m also an assistant professor in the Department of Cardiothoracic Surgery at the University of Pittsburgh School of Medicine and a Cancer Immunologist at the UPMC Hillman Cancer Center.

Daniel Eisenman (01:57): Very good, so with that Paul, Adam should we get started?

Paul Gulig and Adam Soloff (01:59): Let’s go!

Daniel Eisenman(02:04): Okay, so why don’t we just start by simply defining what is gene therapy research. So the definition that I like to use starts with gene therapy, involves the delivery of engineered genetic material to humans, with the goal of compensating for genetic mutations, conferring the capability to produce potentially therapeutic substances, or eliciting immune responses to fight disease. For the folks that are caught up in the technical definitions, when we talk about engineered genetic materials, we’re talking about a recombinant or synthetic nucleic acid molecules as defined by NIH guidelines.

Now just to introduce folks to the booming growth of gene therapy, bear in mind that just less than a decade ago, gene therapy research was really limited to major academic medical centers. We’re talking early stage, early phase trials, very experimental, under very controlled limited conditions, and things have grown dramatically. The FDA issued the approval for the very first FDA-approved gene therapy in 2015, which was a genetically-engineered virus for use in melanoma. There have been a dramatic increase in the number of FDA approvals. And, the FDA is actually expecting to have approvals issued regularly by the year 2025. Now, with that said, Paul, Adam, what do you think are some of the factors that have contributed to the exponential rise of gene therapy research?

Paul Gulig: (03:41): Well, you know I think something that really needs to be emphasized, and it really isn’t germane only to gene therapy, but it’s decades of very basic, fundamental research that have shown us how ourselves work physiologically and the genetic basis for that, and as a microbiologist as well, I think how we understand bacterial and viral pathogens and what it takes for them, you know to cause disease.

So, the thing I would start off by emphasizing is a lot of people might immediately jump to our ability of doing recombinant genetics, which is on the end side of gene therapy. But without a very fundamental basic understanding of how our cells work and how the microbes that cause disease work – especially how cancer works – we wouldn’t even know where to begin to start with gene therapy.

Adam Soloff (04:34): I fully agree. I mean, what we can do now is exceptional, but this has been built off the hard work of brilliant scientists for decades and decades that we have the basic, fundamental knowledge of how the genetic code works, and how we can manipulate it. So this didn’t occur overnight, and I like to think about: in addition to just the knowledge that we’ve enhanced our understanding as humans, we’ve also increased our technical capacities. I always laugh that I got my first cell phone when I was in college.

I mean the pace of technological development is exponential and that translates to medicine to, the fact that we talked about personalized medicine in genetic engineering and we can do this in an effective and a safe manner, is something that would have been science fiction.

Daniel Eisenman (05:21): I love, how you just expressed that, and I’ll tell you we didn’t collaborate on this, we didn’t compare notes in advance. I actually have a slide for when I talk about this subject that talks about FDA approvals and how gene therapy is no longer science fiction. But, you know, there’s still a good amount of meat on the bone in terms of talking about just the massive growth that’s going on here.

So, I mentioned the first FDA approval for gene therapy was in 2015. In 2017, there were three approvals issued. And then things have grown to the point where just looking at where we are right now, there were two FDA-approved gene therapies in the month of March alone. Both of them involved genetically modified cells, human cells, for use in B Cell Cancer. So, when we talk about personalized medicine for cancer, that’s definitely something that we can talk about.

And going back to the slides that I mentioned previously, I could fit all of the approved drugs or approved gene therapies on one slide and have ample room left over. Now I’m at the point where I actually have to break them out into separate slides based on disease indication, because there are so many approved gene therapies.

Daniel Eisenman (06:45): In 2019, the FDA made a statement – so this was then-Commissioner Scott Gottlieb and Peter Marks, who’s the director of the FDA Center for Biologics Evaluation and Research – they issued a statement saying that gene therapy is at the point where monoclonal antibodies were in the late 90s, and the mainstreaming of monoclonal antibodies are currently seen as the backbone of modern treatment regimens. And that’s where they anticipate gene therapy is going, as a backbone of modern treatments. In that same statement that said that they expect there to be 10 to 20 FDA approved gene therapies per year by 2025, so this area is definitely experiencing booming growth.

Adam Soloff (07:34): Absolutely, I think you know we might touch on it later, but it’s also impressive when you think about our current response to the COVID pandemic, right? And that you’ve gone from many, many, many trials that are phase ones and phase twos, which are small amounts of subjects to test for safety and test for proper responses, but now we’ve seen genetically-engineered products in million, hundreds of 10s of millions, hundreds of millions – where are we now?

Daniel Eisenman (08:01): Exactly so many people may not be aware, but the front line vaccines against SARS-CoV-2, or you know COVID-19, are vaccines that contain engineered genetic material they required IBC review and now, and Adam is right, as of April 2021 we’re over 100 million vaccines administered in the United States. So we’ve come a very long way from technology that was limited to early phase trials in major academic medical centers under highly controlled experimental conditions. Now you can go and get a vaccine with emergency use authorization throughout your community, including large chains of pharmacies.

Paul Gulig (08:48): I just want to put a placeholder in. I know a little later we’ll talk about the impediments to the acceptance of gene therapy, but I think when the COVID mRNA vaccines came out, we know that in the social media, especially, there was a lot of misconceptions about what was happening there, with mRNA being injected into ourselves and with the adeno vector COVID vaccines actually delivering a gene that was being expressed. I think we have a long way to go in terms of educating the public into what different forms of gene therapy are and what they are not. Now, the spectrum is very wide. From adding genes that will be, hopefully, expressed for the lifetime of the patient to where the mRNA’s are hanging around maybe only for hours, but still doing their job and in an effective way. So I agree that the COVID vaccines have thrown this to the forefront.

So I think those of us in the field as educators and as people involved in the oversight, it’s really incumbent on us to be educators of society in general. I think we’re kind of behind the curve there but, I think we can do it.

I’m going to play the role of moderator here and bring us back to what our initial issue was, and that was factors that contributed to the exponential rise of gene therapy. Because, I just wanted to mention a couple of things that really opened the door. One of them, of course, was our ability to genetically manipulate human cells. As a microbiologist, I have to tap my field – although I’m not virologist, I’m a bacteriologist – the ability of using viruses to deliver genes into human cells to change their genetic makeup. We’ve talked about it at our IBC meetings: many, many, many cancer therapies with genetically engineered T cells called, CAR T-cells. And, of course, the Johnson and Johnson and AstraZeneca COVID vaccines are gene therapy using adenovirus.

And the other thing I wanted to throw in which again is, is kind of a two-edged sword is the whole CRISPR cast genetic editing which really opens the door for personalized medicine. To be able to go in and change single letters of the genetic code to correct somebody’s genetic defect in a very, very personalized way. The tools are there that have really exploded over the last five-to-10 years, so kind of on a technological side it almost seems like the sky’s the limit.

Daniel Eisenman (11:31): I would completely agree. Talking about how treatments in oncology have come a long way, and with gene therapy how it’s very targeted and specific and personalized. If you consider chemotherapy, you get a chemical whether it’s a pill or an intravenous infusion, and it goes fairly systemically, which is part of the reason you have a lot of toxicity issues. The drug doesn’t just go to the cancer. One of the benefits of using gene therapy for more targeted and personalized cancer therapies, is you don’t have those concerns. Paul mentioned Chimeric antigen receptor T cells, or CAR T-cells, and they are very personalized in the sense that for the autologous therapies, they actually come from the research subject, they’re genetically engineered to reprogram the T cells to make it specific to that type of cancer that person has, and they’ve been phenomenally successful, particularly in the B-cell leukemia and lymphomas. There have been, I believe at last count, seven or eight FDA-approved CAR T-cell products, specifically for B-cell leukemias and lymphomas – and, particularly in cases of resistant or refractory disease.

So, these are research subjects and patients that have pretty much exhausted standard of care therapy. Unless some unexpected circumstance or miracle arose, they had a very poor prognosis. These CAR T-cell therapies have been phenomenally successful.

Paul Gulig (13:22): My wife is a pediatric hematology oncology nurse and so she’s given chemotherapy to her patients for many years. She’s often commented on how in the future, we would look back on medical practice of administering these highly toxic drugs to try to treat people’s cancers. As you mentioned, the engineered CAR T-cells specifically target the cancer cells of the patient really has revolutionized that. There’s only a few of them that had been FDA-approved. But, as we know, there are a multitude of clinical trials going on.

And I don’t think we know from our trials and, as you mentioned, they’re reserved for people who have failed the normal treatment. But I think that pretty soon, they will become the normal treatment and the chemotherapy will be on the backside only for those people who failed.

I’d like to kind of segue into non cancers. We focused on cancers, but you know there’s a whole host of genetic issues, such as sickle cell, hemophilia, autoimmune diseases, and things that we have the capability of going in and either correcting the mutated genes or providing the normal copy of the gene to the people. And again, different people will have different mutations. To me the challenge is how do you do clinical trials on the gene therapy when the product might be a little bit different from patient to patient.

Adam Soloff (14:55): I think when you’re talking about that type of gene therapy, it’s almost a completely different ballgame. Because, what we’re talking about with whether you have a CAR T-cell therapy, or an mRNA that’s used as a cancer vaccine in a dendritic cell, these are not permanent products, right? Well, we actually hope that the CAR T-cells engraft and that they live in that person for quite a while, and that’s actually associated with better treatment. But when you talk about correcting diseases that are caused by genetic alterations, now you’re actually talking about changing a person’s genetic code, or the genetic code of those cell types, and I think that warrants quite a bit more stringent consideration.

Paul Gulig (15:38): I agree, they are fundamentally different, and kind of going for full circle back to the COVID mRNA vaccines, the genetic engineering is basically gone within hours of getting the vaccine. On the other hand, if you’re trying to cure somebody’s sickle cell disease, you want their red blood cell producing cells to be permanently changed and to make normal red blood cells. So again, I think that in trying to educate the lay public on this, it’s really going to be a challenge. That was one of the concerns with the COVID vaccines is, “you’re changing my DNA”, which of course wasn’t true. But, trying to tell them: “No this is something that’s going to happen very briefly, but it’s going to have a long-lasting effect on you”. But at the same time, if you’re telling somebody with sickle cell once we give you this, you may not need to be treated again for the rest of your life and you’re going to live a completely normal life.

Daniel Eisenman (16:37): I think that’s part of the benefit of IBC review, that maybe a lot of people are not aware of. The FDA looks at whether a drug is manufactured under the best manufacturing practices and is it safe and effective. The IRB looks at human subject protection, whereas the IBC really looks specifically at the risks associated with the engineering genetic material, what are the risks of the research subject? In that regard, the IRB in the IBC work very collaboratively, but we also look at the risk to the research staff, the facility, the community, and the environment, because bear in mind that many of these engineered genetic materials either contain infectious material, or genes derived from infectious material, or they’re manufactured using infectious material. Genetically engineered viruses are commonly utilized, because if you think about how a virus works it’s unable to reproduce on its own, it has to be able to deliver its genetic payload into a host cell in order to hijack the machinery of that cell to then be able to make progeny viruses. The genetically engineered viruses used for gene therapy are typically engineered in a way where they lack the genes needed to produce progeny viruses or cause disease. The resulting weakened virus essentially functions as a genetic syringe to deliver engineered genetic material.

Adam Soloff (19:57): I do think it’s extremely important to convey how much rigor goes into evaluating the safety of these products, and that can’t be minimized. You have a subject, who is putting their faith and trust that you are looking out for their best interest in their health. It’s critically important that there’s transparency there and there’s an understanding of how these trials are actually run. I don’t think is apparent to the public that you start with a phase one of a couple subjects. Then when that seems safe, you move on to a slightly larger study with a couple more, and a couple more. These take years and quite a great deal of effort, all the while with patient safety in mind. These aren’t genetic engineering, it’s not something that’s done frivolously; we’re not trying to change people’s eye color, we’re trying to cure lethal diseases, right?

Paul Gulig (20:58): Since we’re winding down, I think one of the things that will be very important in conveying to the public of what current gene therapy is not, and that is what we call the germline changes, where you basically change somebody’s genetics so that will then get passed on down to their children. Basically, fundamentally changing the human genome, which is really universally banned right now for all research. I think that’s the stuff in science fiction movies. I’m an educator, and I think that education here is really a key for us to be able to move forward and get people to accept it in a positive way, to open the door for the improvement of their own health.

Daniel Eisenman (21:52): Correct, and we are in the beginning of a golden age, not just specifically gene therapy, but specifically in terms of vaccines against infectious diseases and cancer. We’re about to see a phenomenal boom in terms of diseases that were previously not preventable, not treatable. It’s a very exciting time and personally I love having a front row seat to all of this exciting research.

Adam Soloff (22:24): I’m thinking, you know, we talked about the future here right, and again, we’ve been I don’t know how many combined years of history and recombinant DNA we have, but I love seeing these things roll out to the public. Last week, Oxford and AstraZeneca showed really positive data with a vaccine against Malaria, which is the same recombinant DNA and you’re like, wow if you had a vaccine it presents low 70% efficacy, you will save millions of lives, right? That’s amazing to see this come to fruition.

We’re seeing this with COVID – the COVID vaccine is saving lives. I’m excited we can talk about the latest and greatest of engineering T cells for cancer or correcting mutations and sell a lot certain cells to alter disease. I’m excited to see what we can bring to the global public at scale now. As time goes on, as our tech develops, as we get better at it, some of those more personalized techniques and those personalized treatments are going to be scalable to be delivered. Instead of just your specialized academic medical center that can be delivered at the local pharmacy, or mass produced and sent out a couple cents a shot around the world. We talked about this as a tool that does have the potential to revolutionize global health, as we did with antibiotics, as we did with vaccines, as we did with handwashing. This might be the next wave of how we make people healthier how our quality of living – this has that written all over it to me.

Daniel Eisenman (24:06): Exactly right, and so talking about the top two causes of pediatric and death in the world, Malaria is number one and respiratory syncytial virus is number two. We’re looking at clinical trials for vaccines against these diseases. What if we develop safe and effective vaccines that make the top two causes of death in the world vaccine preventable? What kind of effect would that have for public health, global public health, and what effect would have on humanity? That’s really astounding.

Adam Soloff (24:41): That’d be amazing.

Daniel Eisenman (24:42): But I see that we’re, we’re running low on time. I want to give a huge thanks to Paul and Adam for joining me today and engaging in this important conversation. Also want to extend a thank you to all of those of you who are listening.

Paul Gulig (24:09): And I want to thank you for letting me be a part of this conversation, it’s been a lot of fun.

Adam Soloff (25:04): Yeah, this is great, you have this sense that we could do this for a couple hours.

Daniel Eisenman(25:11): Oh, and when I first looked at, when I told you this would be just like the three of us hanging out at a bar, but you know there won’t be any beer involved, but with that we conclude the third episode of Advarra In Conversations With. If you enjoy today’s discussion, keep a lookout on our social channels and on and Advarra.com for our next episode and thank you all for listening.

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