What’s Next For Gene Therapy?

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With the production and distribution of mRNA and adeno-associated virus-based vaccines at an unprecedented scale, gene therapy has finally come of age. This technology has the potential to revolutionise medicine itself, but many challenges still need to be overcome if gene therapy is to realise its full potential. In a virtual event organised by STAT, Damian Garde sat down with three experts in the field of gene therapy: Dr Seng H. Cheng, senior vice president and chief scientific officer, rare disease research unit, Pfizer; Dr Nicole Paulk, assistant professor, biochemistry and biophysics department, UCSF; and Dr Glenn Pierce, interim CSO, Voyager Therapeutics; entrepreneur in residence, Third Rock Ventures; vice president, medical, World Federation of Haemophilia. They address some of the main hurdles currently facing gene therapy technologies. Here is a summary of what they discussed:

What is the next biggest barrier in the way of gene therapy?

The speakers agreed that one of the biggest hurdles for gene therapy continues to be manufacturing. We need more manufacturing plants to produce more of these therapies, but right now, many gene therapies are not scalable because the manufacturing process is too complex. In particular, we need new ways to produce adeno-associated viruses (AAVs), which are currently made with techniques borrowed from the field of monoclonal antibodies.

In addition to improving the manufacturing process, we also need to gain a better understanding of the host immune response against AAVs and why this varies from person to person (this refers to the fact that the immune system sometimes attacks the viral vector that carries the gene therapy to the cells, thus reducing the treatment’s effectiveness). We see this immune response in most gene therapy studies, and it can affect the expression of the therapeutic genes. Ideally, we need to find a way to control this immune response. We are also going to need significantly more potent AAV vectors for certain diseases of interest.

How much of a barrier is the tolerability of gene therapy?

So far, all gene therapies have had problems with toxicity, meaning that there is a limit to how much gene therapy can be safely delivered. In some cases, the use of immunosuppression might be able to help with this, but a more effective strategy may be to find new vectors with fewer off-target actions. For example, we need vectors with reduced targeting of the liver, where toxicity is particularly important.

One thing that will help overcome this problem is improving our understanding of the basic biology of gene therapies, which is still quite poor. Between a vector reaching the cell and the protein coming out, we have ‘almost no idea’ what’s actually going on. If we can fix this hole in our knowledge, we might be able to improve the efficiency of gene therapies and make toxicity less of a problem. Unfortunately, the types of research needed to solve this problem are long and expensive projects that are hard to get funding for. They are also a hard sell for researchers because, in the words of Dr Nicole Paulk: ”understanding the uncoding kinetics of a different AAV capsule is probably not going to get you a cell science or nature paper”.

Poor understanding of the fundamental biology tends to be more problematic for therapies that are more toxic. If a drug is highly effective and safe, we don’t really need to know how it works – only that it does. But when a drug has high toxicity, knowing how it works is important for addressing that problem.

Who is best suited to tackle these problems?

Partnership between all of the stakeholders is important when it comes to expanding on an emerging field. It’s not exclusively a large or a small company domain, but mix of the two, perhaps depending on the nature of disease. Large companies are better placed in situations where large amounts of vector are required, but new innovations for tackling new diseases are more likely to come from smaller biotech companies.

How can we overcome the price of gene therapy in order to reach the primary care space? How do we make gene therapy mainstream?

If gene therapy is to become ‘mainstream’, we need to solve the pricing issue – there’s no way around that. We cannot move forward with therapies that cost $2-6 million per infusion. Improving manufacturing efficiency will help drive down costs, and as touched on already, this is one area that should be tackled first. Many companies also currently have a ‘cookie cutter’ mindset when it comes to picking which diseases to target, electing to attack diseases and organ systems for which our current vectors are most suitable. This means that many companies are going after a narrow set of diseases. While it is great for those affected to have multiple therapies to choose from, it would be good to see more flexibility and creativity in this area.

It is also pointed out that while gene therapies are expensive to make, the actual price tag for most gene therapies still far exceeds the manufacturing costs. This is understandable as companies must still recoup development costs and account for the risks that are involved in bringing any therapy to market. However, there may be room to narrow this cost gap. The widespread adoption of gene therapy is also going to require us to demonstrate higher levels of reproducibility and safety.

How confident are we that ‘one and done’ gene therapies will continue to be safe and enduring in the future? Is there a risk that people will need boosters or side effect mitigation years down the line?

We simply don’t know the answer to this question, as there’s no available human data. Animal data does at least suggest that expression remains stable for a very long time. If expression does wane in 20 years time, we will have forewarning of this, and there are people working on redosing strategies for this scenario. But again, we simply don’t have the necessary data to know whether declining expression will be a problem, and optimism on this issue varied among the speakers.

When attacking a specific disease, how do you go about choosing a suitable gene therapy vector?

For a vector to be suitable, it needs to have the carrying capacity to deliver the genetic material in question. The vector needs to be able to reach the target organ, and antibodies against your vector must be sufficiently rare amongst patients with the targeted disease. If too many patients have antibodies against viral vectors, then mRNA based gene therapy may be necessary. Many other factors, such as the nature of the diseases and the target organ, are also important. For example, most mRNA based therapies delivered via lipid nanoparticles have so far only been effective in the liver. All of these technologies have their applications and it is unlikely that any one of them is going to usurp the others for the foreseeable future.

What can the federal government do to best support gene therapy research?

More funding! As mentioned previously, we really need to understand the fundamental biology of viral vectors more. We don’t necessarily need a new NIH institute, just more funding, perhaps special grants specifically for this research within existing institutes. The accelerated development of the COVID-19 vaccines has demonstrated that when there is political will, great scientific advancements can be made that were previously considered to be very daunting and difficult.

What will the state of gene therapy be 10 years from now?

AAV will still be here 10 years from now, but perhaps not in their present form. All 1st generation AAVs may have been modified to reduce off target actions, and we will hopefully understand the biology well enough to design more efficient treatments. With that being said, there is evidence that current AAVs are able to target the heart and the central nervous system, which may open up quite a number of new diseases for targeting.

We will hopefully have developed better manufacturing techniques. It is likely that gene therapies will still primarily target monogenic diseases, but we may begin to see broader applications. Intravenous treatments may be less common as new methods of administration become available.

We may also begin to make use of companion therapies alongside AAVs, such as immune modulation and also modulation of the extracellular matrix (the protein scaffolding between cells), which could make it easier for AAVs to deliver genetic material to certain hard to reach cell types.