In this insightful interview, leading experts in gene therapy, Franco Locatelli1 and Luigi Naldini2, discuss the transformative potential of gene therapy in treating genetic blood disorders and other severe diseases.
Luigi Naldini1, Director, SR-Tiget, San Raffaele Telethon Institute for Gene Therapy; Professor of Tissue Biology and Gene Therapy, Vita-Salute San Raffaele University Medical School, Milan, Italy.
Franco Locatelli2, Director of the Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù Children’s Hospital; Full Professor of Paediatrics, Catholic University of the Sacred Heart, Rome, Italy.
What initially sparked your interest in gene therapy and what continues to motivate you today?
Locatelli: I am interested in gene therapy, which includes both gene editing therapy and genome editing, because I strongly believe it is an important therapeutic option with the potential to provide a curative strategy for many genetic disorders, different cancers, and selected type of autoimmune diseases. In particular, I have participated in trials of gene editing therapy for beta thalassaemia and sickle cell disease in trials of gene addition therapy for thalassemia and adrenleukodystrophy. The outcomes in terms of safety and efficacy have been promising, especially for thalassaemia and sickle cell disease, as gene editing and gene addition therapy show an incredibly high success rate.
Naldini: Well, that goes a long way back, more than 30 years for me, when I became fascinated with the idea of genetic engineering. New tools were becoming available for attempting gene transfer with the perspective of a therapeutic application. Since then, I have focused my research on this field, fascinated by the combination of state-of-the-art technology, such as gene transfer, and now gene editing with the intriguing biology of stem cells, like haematopoietic stem cells, that allows tissue regeneration and transplantation. Leveraging on these advances, makes it possible to design new, transformative therapies for severe or lethal diseases for which we have no other therapeutic options.
Can you provide an overview of the key advancements in gene therapy that have made the "bench to bedside" journey a reality in recent years?
Locatelli: The key advancements for gene therapy, particularly gene addition therapy, have been represented by the use of self-inactivating third-generation lentiviral vectors, which have proven to be safer and more effective than retroviral vectors. Another key point is the optimisation of the transduction process. Thanks to refinements, it has been possible to increase both the percentage of transduced cells and the vector copy number, both crucial factors for optimising the chances of success in gene addition therapy approaches. The availability of the CRISPR-Cas9 system was also a major breakthrough allowing to advance the field of gene editing. In addition, although I didn’t participate in the trial, CRISPR-Cas12 offers the ability to perform highly precise molecular editing without jeopardising the clonogenic potential of haematopoietic progenitors. Overall, gene editing can be considered a form of molecular surgery that enables us to target specific genes, such as BC11A, which is responsible for the switch from γ-chain to β-chain production in haemoglobin. The selective disruption of this gene can be achieved using RNA guides and the CRISPR-Cas9 system, which is key for ensuring the success of the procedure. This precision medicine approach allowed to fully restore the production of fetal haemoglobin (HbF) and, thus, to render patients free from transfusions (thalassemia patients) or from vaso-occlusive crisis (sickle cell disease subjects).
Naldini: I think we've seen a major leap forward with the second generation of engineering tools and gene transfer vectors. Early studies provided proof of principle for the efficacy of gene transfer into stem cells, but the methods were relatively inefficient. As a result, they were limited to treating only a few diseases, and there were concerns about potential adverse effects. New vector systems, especially lentiviral vectors for stem cell gene therapy, have been specifically designed to address these issues and have significantly improved both the efficacy and safety of gene therapy strategies. This progress has driven the field forward, leading to the development of promising haematopoietic stem cell gene therapies for an increasing number of diseases. After up to 15 years of follow-up on hundreds of patients, the efficacy and safety of these treatments have now been consolidated. Of course, we're now entering a new era of genetic editing, which can build upon prior experiences to increase precision and expand potential applications.
What are some of the most significant challenges you see in translating gene therapy research into effective treatments for patients?
Locatelli: For the genome editing trials, they refer to the treatment of subjects aged between 12–35 years. We are still awaiting results for paediatric preparations as well as for patients above the age of 35. However, the two main regulatory agencies, the FDA and the European Medicines Agency (EMA) have authorised the treatment for patients above 12 without any upper age limitations. In the future, we will have real-life data on the safety and efficacy of the approach for those over 35. Another relevant challenge is the affordability of the approach, particularly in countries with limited economic resources. This presents a potential risk of unequal access to treatment in richer versus poorer countries. In the future, efforts must be addressed to identify novel strategies to render these highly innovative therapies available for all patients across the world.
Naldini: These treatments are transforming clinical care. They offer unique benefits, but they also come with significant challenges. The complexity of the therapy is a key factor. We're not talking about pills or biologics, we're talking about modified viruses, and more often in haematology, modified cells with viruses. The manufacturing process is very complex and highly personalised. In most cases, we use the patient’s own cells, which makes the process more complicated and riskier. It also depends on the initial cell harvest from the patient, which may not always be efficient. This raises concerns about the sustainability of these treatments.
We know these therapies work, but the real challenge lies in making them available to patients and keeping them on the market, especially due to the high cost of manufacturing and often the rarity of patients, which challenge economic sustainability even when claiming a very high market price. Additionally, these treatments are often "one-and-done," meaning that a single administration can potentially provide a lifetime benefit for the patient, which is great. However, from a pharmaceutical perspective, it’s difficult to translate this into an efficient payment model. Among the models being explored are linking the payment to the success of the therapy and spreading it over several years of follow-up.
In your upcoming keynote at EBMT 2025, what are the main themes you hope to highlight regarding the current state of gene therapy in haematology?
Locatelli: During my keynote, I will address the issue that this treatment can potentially be offered to any patient, provided there is a sufficient stem cell reservoir and limited iron overload in the tissues. This clearly represents a great advantage compared to allogeneic stem cell transplants, where a compatible donor is required to optimise the chances of success. Additionally, I emphasise that the use of gene editing is associated with a better safety profile compared to allografts, meaning that the treatment can also be offered to patients, including those above the age of 14 in whom allogeneic stem cell transplant is not routinely considered in view of the considerable risk of transplant-related mortality and to patients without HLA-identical donors.
Naldini: What I’m trying to do is carefully assess and balance the established strategies of gene therapy in the field, such as gene transfer into haematopoietic stem cells, with emerging approaches like gene editing. The goal is to evaluate the relative benefits, both known and unknown.
We have a longer-term clinical experience with gene transfer technology, and we’ve learnt a lot about its safety, potential adverse effects, and the biological mechanisms underlying genetic engineering. In contrast, we have much less knowledge and experience with gene editing technology. While gene editing offers exciting new opportunities, we must approach it with caution because we don't fully understand the underlying biology yet.
So, the question is, how do we choose between these strategies, gene transfer and gene editing, when they are available for the same disease? What would be the most ethical and scientifically sound approach to ensure the best possible benefit and safety for the patient?
How do you foresee gene therapy evolving over the next decade, particularly in the context of blood disorders and stem cell-based therapies?
Locatelli: I am confident that the approaches of gene addition therapy, and in some selected cases, genome editing, will be translated to other inherited diseases. Around the world, there are several efforts to validate the results obtained in patients and subjects affected by other inherited diseases, including primary immune deficiencies and certain metabolic disorders. By using different approaches, such as in vivo gene addition therapy, we will have the opportunity to potentially offer curative treatment to patients, for example, those affected by inherited coagulation disorders like haemophilia.
Naldini: I expect that most of these treatments could become standard of care, at least for genetic diseases, where they offer a safer alternative to allogeneic transplants. This is primarily due to the safety of using the patient’s own cells, which eliminates the risk of graft-versus-host disease. Another important point is that gene therapy might even enhance the benefits of treatment compared to allogeneic transplants. For example, by overexpressing certain gene products in diseases like storage disorders, we may see improved outcomes. As a result, gene therapy has the potential to become standard care for a growing number of diseases. Additionally, a key aspect to watch is reducing the burden of the conditioning process. There are many emerging biological strategies for conditioning patients before the graft, and the gentler and less genotoxic these strategies are, the more we will be able to fully leverage stem cell treatments.
As gene therapy continues to progress, how do you see its potential to impact the long-term management and possibly even the cure of genetic blood disorders?
Locatelli: It's clear that the availability of these potentially curative therapies will change the therapeutic landscape, impacting several types of patients and their quality of life. For example, in the gene addition therapy and genome editing trials that I coordinated, there was clear evidence of an improvement in patients' quality of life. Genetic counselling will certainly also be influenced by these approaches. Couples who may start a pregnancy with evidence of a fetus affected by, for example, thalassaemia can now decide to continue the pregnancy without interruption, knowing that there is a highly effective and widely available therapy to ensure the future child will become, thanks to these innovative therapies, free from the clinical signs, symptoms, and manifestations of the disease. The real challenge, as I mentioned before, is making these therapies available worldwide. It's essential that they are not limited only to patients in countries with better socioeconomic resources. It is a matter of ethical and moral justice to do everything possible to make these approaches accessible to patients in less fortunate countries, both economically and socially.
Naldini: I believe these treatments have the potential to replace current strategies. As we gain more confidence in manipulating and transplanting stem cells, we can expect to see true long-term benefits. We already have data from patients treated 15 years ago with the first gene therapies, and we continue to observe stability in the engineered haematopoietic-engineered graft. In the vast majority of cases, we see polyclonality and no expanding clones. Based on our current understanding, this represents healthy haematopoiesis. We will and continue to monitor and document its long-term resilience and response to aging, as we may expect these patients now to achieve a near normal life span. Overall, I think we are in a position to see this as a radical curative treatment for at least a good fraction of genetic diseases that belong to the haematology and metabolic area.
Editorial Team: 