Be a Little Different

Luigi Naldini has always been fascinated by research. After initially focusing on signal transduction, he became intrigued by the gene therapy field – where the drive to try something new led to the development of lentiviral vectors for use in commercial gene therapy. 

How did it feel to receive the Lifetime Achievement Award at Phacilitate 2024?
 

It was very rewarding – as with any award! Gene therapy has been neglected for so long, but now there is appreciation from all over the scientific industry. Early on, there were very few of us working and believing in what could be done with gene therapy. Now, there is much better recognition. Although an award goes to a single person, that person doesn’t deserve all the credit. This award really goes to a whole team of people who have been involved in different stages.

Have you always wanted to be a scientist?
 

I always loved science, but early on it was more about nature and wildlife. In high school, I became more familiar with the emerging concept of molecular biology. At that time, there was no real understanding of DNA and RNA, so it was like an entirely new world was opening up – I found that very attractive. I ended up going to medical school, which, at the time in Europe, was a common path if you were interested in a research career in the biomedical area. Although I am an MD, I rarely practice or conduct clinical work. I am more interested in basic science and translational research.

How did you get into gene therapy?
 

After my MD and PhD, I started work on signal transduction. Back then, we were uncovering the basics of growth factor receptor tyrosine kinase, but I wanted to take a new route. I came across a review about the emerging area of gene therapies by Richard Mulligan (Harvard). After the early hype of gene therapies and the lack of results, he explained that we needed to go back to the hard science.

I was attracted by this idea and I wanted to join the field. I went to the US and I applied to Richard Mulligan’s lab, but I didn’t get the role! Over the years, I became very close to him and he always said, “Too bad you couldn’t come to my lab.” 

And I would reply, “I could have come to your lab, but my application was rejected!” Fortunately, I was also interviewed at the Salk Institute and ended up in the lab of Inder Verma.

Why focus on lentiviral vectors?
 

At the time, there was discussion around current vectors, such as the gamma retroviral vector, not being very efficient. On the floor above me was the lab of Didier Trono working on HIV. It was early days for HIV and there was a lot of work focused on understanding this deadly retrovirus, which was very efficient at infecting human cells. We thought, why not try creating a vector from HIV? I was interested in starting something from scratch in gene therapy rather than joining something that was already going on, so building a new vector was very appealing. Though we never dreamed it would become so useful!

I worked for two years on this project – and it was very difficult at the beginning, particularly as it was a new area for me. I spent at least a month in the library, browsing literature (which is amazing to think about today, given that you can do that in a matter of days using the internet!).

We tested the lentiviral vector we had developed in the brain of a mouse. Could we prove transfection of a neuron? The “eureka” moment was when we got that neuron shining with GFP. It was a big accomplishment – and after that I planned to return to Europe. However, a biopharma company was interested in licensing the technology for product development.

I resigned from my position in Europe and began working with the company to develop the vector for clinical trials in humans. However, the whole field came to a halt because there were reports of tumors developing in patients treated with a gamma retrovirus in Europe. Theoretically, we should have anticipated this but there was not high recognition of the risk at that time. Many companies were scared away from gene therapy – including the company I was working with.

At this point, I returned to academia in Italy and I continued to develop the technology on an academic basis – thanks to funding from the Telethon Foundation and other sources. We also collaborated with researchers in France and eventually we took our lentiviral vector into clinical testing and showed that it was safe.

Paradoxically, an HIV-derived vector was safer than the earlier gamma retroviral vectors! We really did work hard to disable the original virus and improve the safety – but the results went beyond expectation. If treated early enough, children can now be cured of very deadly diseases. Our work attracted people back to gene therapy – including big pharma. Together with the Telethon Foundation CEO we spoke with GSK executives and this led to an alliance for the development of hematopoietic stem cell gene therapy. We developed a handful of successful treatments with them, including the first ex vivo stem cell gene therapy approved worldwide.

All of this work took more than two decades.

How did it feel when lentiviral vector therapies made it to market?
 

Progress doesn’t happen in a single moment. Yes, early experiments can have a “eureka” moment but it takes time to bring this to humans. When you see results in patients and the disease doesn’t seem to be appearing, you need to wait months before you can be sure of the results. It also then takes time to get to market. But it feels amazing!

The whole experience has been a learning curve for us as well as the industry. I feel very lucky that I’ve been so closely involved, from the early steps on the bench, to clinical, and then to market. I’ve also been able to see the challenges from both academic and industry levels.

Where does the industry go from here?
 

We are finally at the point where gene therapy is an established treatment – but mostly for some rare genetic diseases and some types of blood cancers. There is a big need to streamline the process through industrialization, and to address cost and accessibility.

There is also a lot of hype now around gene editing, which has potentially broader application than a gene addition, but it’s early days for understanding its power. Until now, gene editing, to a certain extent, has been leveraging on what had been done with gene addition and addresses the same targets, such as hematopoietic stem cells, T cells, the liver and retina. There is still limited capacity to deal with other targets. Gene editing is great but we still can’t target the heart or the brain – because of challenges in delivery, which are just as much of an issue today as they were 30 years ago. There is excitement around nanoparticles and other innovative delivery vehicles, but most of these currently work for the liver. To realize the promise of gene editing, we need to have better targeting in vivo – scientifically, this remains a big challenge.

Going forward, we also need to continue to be careful about the risk–benefit balance for patients. There are now many tools to choose from and patients must be protected from testing innovations that might be moved to the clinic too early. I would like to see new technologies tested in new diseases that have no other options, rather than going for the same indications. Companies prefer the latter option because it is easier for them to see if the new treatment is really better or not. But what if it is not better for the patient? We must be cautious.

Do we need more intense collaboration to move forward?
 

What we have achieved today in gene therapy is the result of academic research, charity funding (crucial), and involvement of industry – from small biotech to big pharma. While industry was too afraid to commit in the early years, a network of institutions and European grants helped create a community collaborating to the development of cell and gene therapy.

Collaboration must continue – but we also need open transparency. No single treatment or tool is perfect, and there will always be advantages and drawbacks for each of them. If there is a problem with a tool, it is much better to acknowledge that upfront rather than cover it up. There is the risk of the field moving into a more protective, business and venture capital driven model. We have managed to achieve so much today because there has been data sharing and open discussion from the very beginning. Without this, we risk building a culture of suspicion. We must be open about the risks and not oversell the benefits.

What advice do you have for scientists who are just entering gene therapy research?
 

First of all, I would encourage them to enter this area because it is very exciting. It can also give you a broad translational view and help you understand the rationale behind what we do as scientists. I would also recommend people to spend time in academia because basic science understanding and training is key. Today, most young scientists go to industry because of better salaries, but I believe that the best way of doing this type of science is to maintain a strong focus on the underlying biology and address the real challenges. Spending time doing postdoctoral training in a good academic lab to really understand the key points of the field. From there, you can then look at new strategies and be creative.