Interview with Professor at KTH Johan Rockberg

GeneNova aims to reduce the manufacturing costs of gene therapy by a factor of 100

"I believe that there are many diseases that will be treated with gene therapy in the future."

The GeneNova project, in which CombiGene is a part, aims to establish a common manufacturing protocol for academia and industry, and to reduce today’s manufacturing costs of gene therapy by a factor of one hundred! The implications for academia, industry and healthcare are potentially revolutionary. With such a large reduction in costs and a common protocol, significantly more research projects could go all the way to market approval and many more people would be able to access the advanced therapies that are currently limited to a few patients due to excessive costs.

Ingeneious contacted Professor Johan Rockberg at KTH Royal Institute of Technology, who is leading the GeneNova project, to find out more.

What made you and KTH get involved in gene therapy?
“It’s actually very easy to answer. The potential of gene therapy to actually cure serious diseases with one-off treatments and not just relieve symptoms is groundbreaking. The emerging gene therapy means that we are facing disruption in our way of looking at disease, where we hope to be able to cure severe diseases in the future with a single treatment, instead of only relieving symptoms through lifelong medical treatments. However, in order to unleash the fantastic potential of gene therapy, it is necessary to solve the challenges of today’s production methods.”

What are the main challenges?
“The predominant challenge is that it is currently so expensive and cumbersome to produce gene therapies. The high cost means, among other things, that the number of research and development projects in both academia and industry is limited, but above all, the high production cost means that the gene therapies that come onto the market have such a high price tag that, for economic reasons, a limited number of patients can benefit from them.”

Is this where Genenova comes in?
“Exactly! In the Genenova project, we have gathered a broad range of expertise to take a completely new approach to the production of gene therapies. When I say new approach, I really mean it. Our ambition is to reduce today’s production cost by a factor of 100! By giving ourselves this formidable task, we force ourselves to really go deep and seek completely new solutions – just working with fine-tuning within the framework of today’s methods is not enough.” 

What are the overall steps in the production of AAV vectors?
“I would say that there are four key elements. The first step is the production of starting material, i.e. the production of DNA, often in the form of plasmids[1]. The second step is the production of the gene therapy vectors, i.e. the capsules that contain the material to be introduced into humans and that carry with them the DNA that will replace missing genes, repair damaged genes, or increase the expression of existing genes. The third step is to separate out and purify the gene therapy vectors from the material produced. The fourth and final step is quality control – of course, we must have rigorous procedures to ensure that the material produced meets all safety requirements. A fifth element could also be added – storage and transport. Today’s biologics[2] must be frozen to very low temperatures during storage and transport, and defrosted only when they are to be used.”

Are you looking at all these elements within the framework of the Genenova project?
“We are. Let me give you a few examples of the challenges we are working on. The production of gene therapy vectors[3] takes place in reactors where the starting material consists of human cells. This in itself is a major challenge because human cells naturally do not want to produce viruses, which limits the amount of material produced. Right now, we are looking for different ways to remedy this. Among other things, we have changed the properties of human cells so that they do not understand that it is viruses that they produce. We’re also evaluating a tactic that every parent recognizes – we simply bribe the human cells with ‘candy’ to keep them happy. One similarity between human cells and children is that they like sugar, although they also need a balanced nutrition which we also give them.”

“In what we call downstream production – i.e. the work of separating out and purifying the gene therapy vectors – we have taken several innovative steps towards new processes. Alfa Laval has developed completely new separation methods that we are further developing, and in collaboration with Biotage we are developing new ways to make the depletion of the vectors more specific and the purification process more efficient. We are also investigating different ways to dry the gene therapy material to make storage and transport as cost-effective as possible. In terms of quality assurance, we are working intensively with Vironova on new automated solutions in electron microscopy and advanced machine learning.”

How would you describe GeneNova’s ultimate goal?
“Everything we’re doing is aimed at establishing a completely new protocol for the manufacture of gene therapies. The idea is that this protocol will be shared by academia and industry so that research assets can be seamlessly transferred to preclinical and clinical development. For this to be possible, the manufacturing method must be scalable. It should be possible to use the same method to produce small volumes for research and development purposes and large volumes for commercial use. This is one of the most central aspects of what we are trying to achieve and will mean that more research projects will have the opportunity to go all the way to market approval.”

The GeneNova project has been going on for two years. How far have you come?
“That’s right. GeneNova has been around for two years, and we have funding to continue for another three years. We are well on our way to achieving our ambitions to reduce production costs, but we still have many tough challenges ahead of us. GeneNova is a dedicated research project and for every day that passes we generate new knowledge. For example, we have learned a great deal about the behavior of human cells. Our goal of getting down to one percent of today’s production costs can be described as extremely radical, but the goal really drives the innovation within the project. GeneNova has so far created completely new ways of mathematical calculations, new hardware, new culture media, new processes, new capsids, new ways of interpreting studies and new techniques for automated plasmid purification, for example.”

When you look at the participating companies and institutions in GeneNova, you see several obvious names such as AstraZeneca and Karolinska Institutet, but as you already mentioned, Alfa Laval is also participating in the project.
“A traditional industrial company like Alfa Laval may seem like an odd bird in this context, but they are participating for very good reasons! Their expertise in separation technology and the development of new hardware creates new opportunities for us. An important part of GeneNova is also that the project opens the door for a traditional industrial company like Alfa Laval to step into something as delicate as gene therapy. In the future, I can see that several other large Swedish industrial companies may play crucial roles in activities that they do not currently have on the map. For example, there will be a great need for different types of sensors, automation, and wireless technologies. I also believe that there is a lot the pharmaceutical industry can learn from the automotive industry, which has worked for decades to make its operations as efficient as possible.”

If we look specifically at CombiGene, what is their biggest contribution to the GeneNova project?
“CombiGene has been active in gene therapy research for several years, which is extremely valuable for the GeneNova project. Thanks to the company’s extensive experience, CombiGene can help identify what is missing in the production process and what needs to be improved. The company also has extensive experience in designing preclinical studies and is involved in the work carried out on models for diseases of the central nervous system at Uppsala University within the framework of the GeneNova project.”

One last question. Are there any special disease areas that will benefit particularly from the emergence of new gene therapies?
“I believe that there are many diseases that will be treated with gene therapy in the future. Monogenetic diseases[4] are an obvious group , but I am convinced that gene therapy will make a significant contribution to diseases such as cancer and diseases related to the central nervous system, to name a few.”

GeneNova is a unique innovation collaboration created to develop adenoassociated virus-based (AAV) gene therapies. The project is co-financed by Vinnova, academia and industry with KTH as host. The project runs for five years and aims to develop completely new strategies for the development and production of advanced gene therapies. 

The collaboration is supported by Sweden’s innovation agency Vinnova and project partners with just over SEK 110 million during the project period 2021-2026. The companies and institutions involved in the project are: Alfa Laval, AstraZeneca, Biotage, CombiGene, Karolinska Institutet, KTH Royal Institute of Technology, Uppsala University, Vironova and Ziccum.

[1]Plasmids are ring-shaped DNA molecules that are often found in bacteria (prokaryotes). The plasmid often carries a relatively small amount of information (genes) and can thus be easily transferred between bacteria.
[2]Biological medicines are products whose active substance is of biological origin, such as living cells or tissue, and has been produced or purified from it.
[3]Viruses that are carriers of the genetic information to be administered to humans
[4]Diseases caused by one or more mutations in a single gene.

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