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Discovery & Development Advanced Medicine, Drug Discovery, Translational Science

Understanding the Three Levels of Genetic Medicine

How did you get into cell and gene therapy?

Following my medical degree, I went into research; specifically, molecular biology and immunology – there was no cell or gene therapy! I published several papers on tumor infiltrating lymphocytes: the T cells that recognize tumor cells. This work took place yearsbefore therapies such as checkpoint inhibitors led to the explosion of cancer immunotherapies, so we did struggle to find ways of preventing tumors from evading the immune response. But you might say we and other research teams were building the foundation for what would later become CAR T-cell therapy.

After spending some time working in diagnostics, I moved into biologics. We were engineering monoclonal antibodies – and, at that time, it was the coolest thing you could imagine! In particular, we were focused on anti-TNF therapies. I was the senior medical director for the team behind Humira – the first fully human monoclonal antibody approved by the FDA and currently the world’s best-selling drug therapy. And that’s where I really learned the complementary roles of clinical development and medical affairs. After working with several biotechs to speed up therapy development and diagnostics, I joined ASC Therapeutics as Chief Medical Officer. The company has two main development programs – one in gene therapy (including CRISPR-based gene editing) and one in cell therapy.

Can you give me an overview of your gene therapy development programs?

Our gene therapy program is in Hemophilia A, which is caused by a genetic mutation leading to a lack of the clotting factor VIII. We are introducing the missing gene, using a viral vector, to the liver, which allows the hepatocytes to begin producing the missing clotting factor. With a single infusion, we essentially restore the entire machinery that produces the factor. We also have a gene editing program in Hemophilia A, which is in an earlier stage, and can complement gene therapy with the ability to treat the pediatric population.

I should also mention that we are working on something that we believe will redefine gene therapy – at least in the liver. Consider what happens when you introduce your circular DNA into the nucleus of the cell. The process begins with transcription to produce the mRNA. Once the mRNA leaves the nucleus, you begin the translation into the protein, which takes place in the endoplasmic reticulum. We have found that the proteins produced by the circular DNA do not fold in the exact same manner as proteins transcribed and translated from the chromosome. Sometimes the cell will react against an incorrectly folded protein in the endoplasmic reticulum, which is called the unfolded protein response. This can trigger inflammatory responses against the producer cell and reduce the efficiency of gene transfer. In our clinical trials we will thoroughly assess what role the unfolded protein response plays in the success rate of a gene therapy, and hopefully find a solution to the problem.

Can you explain the main differences between gene therapy and gene editing? What are the advantages and disadvantages of both approaches?

With gene therapy, you’re not inserting the DNA into the actual genome. You insert the viral vector into the nucleus – but outside of the chromosome – to produce the desired protein. In short, if the cell duplicates, you’re not going to maintain that circular DNA and the new cell won’t produce the desired protein. If we take our work in hemophilia A as an example, we know that hepatocytes in adults are very stable, so they should be able to keep producing the protein via the circular DNA we introduce for a long time. We don’t know how long yet – it could be five years; it could be 30 years. But this means we can only treat adults, because younger people’s hepatocytes will divide and lose the circular DNA we have inserted and the new cells won’t produce the clotting factor VIII. Therefore, gene therapy is limited to stable cell populations.

With gene editing, you introduce the gene directly into the chromosome using a tool such as CRISPR/Cas9. And that means any dividing cell will retain the edit introduced by the enzymes and, in the case of hemophilia A, you could treat someone under the age of 18. The downside of this approach is the risk of introducing unwanted – and potentially unknown – changes into the genome. Developers must ensure their gene editing therapies do not introduce harmful off-target effects, which is why timelines can be considerably longer compared with other kinds of therapies.

Do you think cell and gene therapies are more complicated for patients to understand than small molecule or biological therapies? Are patients fully aware of how these therapies work and the potential risks involved?

I think most people have a very limited understanding of their genes, genomics, gene therapies and so on. I also doubt that the average patient would know the difference between a gene therapy and gene editing. But it’s an extremely important distinction because people are often concerned about the ethics of manipulating genes. So we need to clearly explain these issues, and I like to do that in terms of three levels. First, you have gene therapy, which, as we’ve discussed, cannot be transferred to dividing cells. Some patients become concerned when you explain that we will be using a “viral” vector. So we must make sure they understand that this is an harmless or inactivated virus – it is not a pathogen.

Then on the second level you have targeted gene editing, which can be transferred to a dividing cell but could not be inherited by the recipient’s child, for example. Then you have the third level: editing the genes of germinal cells or even embryos. This final level is what people tend to be most concerned about from an ethical standpoint, but this isn’t what the vast-majority of therapy developers are doing or considering.

What more can you tell me about your work on off-the-shelf stem cells?

In our stem cell therapy program, we’re using a new type of cells, called Decidua Stromal Cells (DSCs) to modulate the immune response of patients with graft-versus-host disease. Our pre-clinical and clinical data suggest that the immunomodulatory activity of DSCs is superior to that of mesenchymal stem cells and other therapies.

Decidua stromal stem cells are extracted from the placenta of a woman that has just delivered a baby. These cells play an important role in protecting the fetus from the mother’s immune system, but they can’t simply block everything – some immune cells are beneficial to the fetus (or will be beneficial to the baby). So to distinguish between the two, they must be highly specialized in terms of which cells they let through the blood-fetus barrier. In other words, they already have an immunomodulatory role.  

We have been working for over three years with a team at Karolinska Hospital in Stockholm, Sweden, which has been exploring the potential of these cells in graft-versus-host disease for almost 20 years. We have already carried out the phase I and IIa studies in Stockholm, and we have an exclusive license for the cells which are now being produced in the US, which means we will be able to conduct phase Iib and III studies in the US. These are off-the-shelf, or allogeneic, cells that we do not (currently) manipulate before they are injected into patients showing signs of graft-versus-host following a bone-marrow transplant. The cells modulate the immune system to prevent the host’s cells attacking the transplanted cells.

How should this information be communicated to patients?

Sometimes the best way to do this is to literally sit with the patient and their family and explain, step-by-step, what each of these levels mean and how their therapy fits in. It’s especially important to ensure the patient understands they are not receiving a level three therapy – one that would introduce a change into their DNA that could be passed to their children. People may have heard what happened in China, where gene-edited embryos were implanted into two women. People are worried about this – and rightly so. Patients need to understand that this work is not related to their therapy. There may be genuine safety concerns, or risks they should be made aware of, but it should be clear that ethical concerns over “designer babies” aren’t relevant here.

I also think patient advocacy groups have an important role to play in bridging the gap between the developers of these therapies and the patient in terms of education.

Are there other stakeholders for whom education is especially important?

It is crucial for the success of the whole field that all stakeholders – especially payers – understand that cell and gene therapies are unlike anything we’ve seen before. I think everyone appreciates how “cool” these therapies are and, more importantly, understands the value of a potentially curative, one-off therapy. But we need a wider appreciation of how difficult and expensive it can be to produce these products. The cost of goods is uniquely high for cell and gene therapies.  

What is the biggest challenge facing cell and gene therapies today?

Some companies are charging $2 million for a therapy, which they say is going to be for life – but how certain can we be about that? The final data on durability is missing: we simply can’t know for certain how long a gene therapy is going to last. And, given that uncertainty, how can payers properly evaluate the potential benefit of a therapy? It’s a real conundrum we have as an industry – and it’s going to be 10–20 years before we have more clarity.

But, even assuming we have good durability, there are challenges surrounding payment and incentives – especially in the US where people often shift healthcare providers when they change jobs. Why should one provider pay $1 million for a curative therapy today when the patient might change jobs and switch to a different provider that would reap the benefits? I don’t think this has been resolved. Companies like Novartis are thinking about some kind of insurance pool, but it isn’t easy to get competitors to work together – in any field!

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About the Author
James Strachan

Over the course of my Biomedical Sciences degree it dawned on me that my goal of becoming a scientist didn’t quite mesh with my lack of affinity for lab work. Thinking on my decision to pursue biology rather than English at age 15 – despite an aptitude for the latter – I realized that science writing was a way to combine what I loved with what I was good at.


From there I set out to gather as much freelancing experience as I could, spending 2 years developing scientific content for International Innovation, before completing an MSc in Science Communication. After gaining invaluable experience in supporting the communications efforts of CERN and IN-PART, I joined Texere – where I am focused on producing consistently engaging, cutting-edge and innovative content for our specialist audiences around the world.

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