Gene therapy

To overcome the current limits of gene therapies and open the possibility of treating new diseases, researchers are trying to improve the delivery process so that the genes get to the right organs, without necessarily going through the liver, and targeting so that the genes get to the right cells. To do this, they are trying to improve the techniques for manufacturing capsids, i.e the “boxes” containing the gene within viral vectors (techniques known as “capsid engineering”), but also experimenting with other ways of encapsulating genes, such as nanoparticles.

How can new technologies be developed to optimize the targeting of genes to the right organs and the right cells, whether to improve the efficacy and safety of current treatments or to imagine new treatments? 

Occasionally, some patients develop antibodies against viruses used to deliver the genes, which can potentially block the effectiveness of certain gene therapies. Research is therefore underway to understand how to create optimal immunological conditions prior to injection, in order to ensure that the treatment is effective over time. The aim is to reduce the immunogenicity or increase the immunotolerance to these gene therapy drugs.

What technologies could make it possible to minimize the immunogenicity of viral vectors? What overall therapeutic strategy could be put in place?

While gene therapies historically focused on replacing deficient genes, systems are being developed to allow genes to be “turned on” and “turned off”, and even more difficult, to modulate their expression in a controlled manner. The aim is thus to attenuate the effect of a certain gene whose expression is too strong (e.g: genes whose expression induces eye stress which can be harmful if too intense) or on the contrary, amplify the effect of other genes that are not expressed enough.

What technologies can make it possible to control the expression of a gene? What diseases could be treated with such a mechanism?

The manufacture of gene therapy drugs is very complex and highly regulated by the Good Manufacturing Practices (GMP) standards that apply to ATMPs. It requires extensive expertise and robust processes, the two challenges that still drive the pharmaceutical industry. It should be noted that in recent years, progress in the fields of bioreactors and flexible chains has led to an increase in the manufacturing offer of CMOs (Contract Manufacturing Organizations). Beyond the production itself, the development of the supply chain is, as with any new biotherapy, a key industrial issue: identify and assess suppliers, plan for redundancy, guarantee quality and deadlines, etc.

How can the robustness and efficiency of gene therapy manufacturing processes be improved? What choice should be made between developing internal manufacturing processes or outsourcing via CMOs? How to secure a reliable supply chain?

The model for dispensing gene therapies according to the typology of the diseases addressed is the subject of many discussions. Indeed, some diseases already have established structures, such as centers of excellence, competent and equipped to treat patients by gene therapy. On the other hand, for certain rare diseases, the care expertise does not yet exist and the patient pathway must be completely imagined. This raises, for example, the question of creating centers dedicated to gene therapy – rather than to a specific disease – to optimize product monitoring and experience sharing.

How to support the growth of gene therapy treatment centers? When and how to identify them?

Gene therapies present particularities which often make the construction of a business model and a reimbursement scheme more complex. The challenge is to both be able to demonstrate the value provided by gene therapy compared to current treatments, and to imagine an innovative financing model able to cover the costs of a one-off treatment, which may be equivalent to the cost of several years of expensive chronic treatment. There is also the issue of defining who should bear the responsibility for any failure of such an expensive treatment.

What funding model to adopt for gene therapies? What is the risk sharing between the different stakeholders?

It is key for an industrial player to have a clear vision of its long-term strategy around gene therapies, whether it be the choice of therapeutic areas and targeted diseases, or the technologies to be developed. A portfolio strategy can be based either on a specialization in a specific therapeutic area, or a diversification in many therapeutic areas with more potential, but with greater risks. Indeed, certain technologies, such as mRNA, have a high potential for versatility, i.e they could bring clinical benefits to many pathologies. On the other hand, some diseases, which are multigenic, may require a combination of gene therapy approaches to be treated effectively. Ultimately, it is by evaluating the benefits and risks of each route that manufacturers can build a real portfolio strategy.

What portfolio strategy to adopt for the development of its gene therapies? What are the risks and opportunities for gene therapy in each therapeutic area?

Gene therapy, through the control it potentially offers over the human body, is the subject of important ethical considerations. Thus, germline modification, that is to say cells transmitted to one’s children, is prohibited in most European countries. Overall, it is important that the regulations around gene therapy best reflect the evolutions of societal debates in order to define a clear ethical framework for research and innovations in gene therapy.

What are the regulations in force around the world and what are their differences from one country or region to another? How to adapt your strategy accordingly?