Ivana Trapani: Pioneering Advances in Gene Therapy with ERC Starting Grant
Ivana Trapani, a distinguished young researcher at Tigem, has recently been awarded a prestigious ERC (European Research Council) Starting Grant for her innovative work in the field of gene therapy. Dr. Trapani's research journey began at the prestigious Telethon Institute of Genetics and Medicine (TIGEM) in Italy, where she made significant contributions to the understanding and application of intein technology for gene therapy. Her work at TIGEM laid the foundation for the innovative use of inteins as a method to deliver large genes that exceed the cargo capacity of AAV vectors, addressing a critical challenge in the field.
Addressing the Limitations of AAV Vectors with Inteins
Despite significant advancements, in vivo gene therapy using adeno-associated virus (AAV) vectors remains constrained by a critical challenge: the limited cargo capacity of these vectors, which is less than 5 kilobases (kb). This limitation has prevented the application of AAV vectors for treating inherited diseases caused by mutations in large genes. However, Dr. Trapani's groundbreaking research offers a promising solution to overcome this obstacle and revolutionize gene therapy for a wider range of patients.
To expand the therapeutic potential of AAV vectors, Dr. Trapani and her team have developed a novel strategy that utilizes short protein elements called inteins. Inteins are segments of proteins that can excise themselves from a larger protein and join the remaining segments, effectively splicing the protein back together in a traceless manner. This mechanism can be harnessed in gene therapy: when inteins are fused to the ends of fragments of a large protein, these fragments can be delivered separately via AAV vectors and subsequently reconstituted into a full-length protein within the target cells.
Despite the promising potential of inteins as biotechnological tools in vitro, their application in vivo for therapeutic purposes presents several challenges. Current limitations include insufficient levels of full-length protein reconstitution for some medical applications, a complex design process, and the production of undesired and potentially harmful by-products.
Dr. Trapani's project, NextGeneTx, aims to overcome these hurdles and expand the use of AAV-inteins as a versatile in vivo biotechnological tool for therapeutic purposes. To achieve this goal, her team will employ cutting-edge technologies to:
The therapeutic potential of these evolved AAV-inteins will be tested in both gene therapy and genome editing applications, using human retinal organoids and animal models of retinal diseases. The successful implementation of this strategy will define a new, highly adaptable, safe, and effective next-generation AAV-based approach to deliver large genes, significantly expanding the patient population that can benefit from in vivo gene therapy.
Historical Development and Future Impact of Optimized Intein Technology at TIGEM
The development of intein technology has its roots at the Telethon Institute of Genetics and Medicine (TIGEM) in Italy, where researchers have been at the forefront of this innovative field. Initially explored as a biotechnological tool in vitro, inteins have now been adapted for in vivo applications, thanks to the pioneering work of TIGEM scientists. This technology is currently onder development to AAVantgarde Bio, a groundbreaking biotech company dedicated to developing therapeutic products for the treatment of retinal degeneration.
AAVantgarde Bio, an Italian startup founded by Alberto Auricchio and supported by the Telethon Foundation, has emerged as a leader in the field. The company recently secured the highest round of funding ever achieved in Italy, raising an impressive €61 million. This substantial financial backing underscores the critical importance of intein technology in advancing gene therapy approaches based on AAV vectors, particularly for delivering genes larger than the AAV cargo capacity.
The optimization of intein technology represents a significant step forward in gene therapy, particularly for diseases involving large genes that were previously considered undruggable due to size constraints. By improving the capacity of AAV vectors to deliver larger genetic payloads safely and effectively, inteins have the potential to unlock new therapeutic possibilities for a wide range of genetic disorders.
Given that AAV is currently the safest and most widely used vector for in vivo gene therapy, advancements in intein technology could lead to more effective treatments for numerous inherited diseases. Dr. Trapani's NextGeneTx project is poised to make a transformative impact on the gene therapy field, enhancing the therapeutic landscape for patients worldwide and opening new avenues for scientific exploration and medical innovation.
"When I received the notification that I had won, I had to read it twice to make sure I understood correctly," Ivana recalls, still emotional about the moment. "It was a tremendous satisfaction that rewarded me for so many sacrifices. I was worried that my career path, which had been almost entirely in Italy without extended periods of training or work abroad, might have put me at a disadvantage." However, Ivana's journey was shaped by the opportunity to work at a center of excellence with a strong international profile, under the guidance of one of the most renowned scientists in the field of gene therapy. "Few places in the world would have allowed me to follow ideas from their inception and development in the lab to their transformation into therapies applied to patients, as I did at TIGEM. What more could I have asked for? My career has evolved alongside building and growing my family — I now have two children — and here I am!"
Now, with this new project, Ivana has the opportunity to pursue what she is most passionate about in her work: designing new drugs, optimizing existing ones to make them more effective, and exploring the details that will enhance their impact. "Together with my team, who celebrated this achievement with me, we are ready for this exciting new challenge!"
In Ivana's view, this recognition by the ERC not only validates her scientific efforts but also sends a powerful message that success is attainable through diverse paths, even those that do not necessarily conform to traditional international career trajectories. "This project represents a significant opportunity to demonstrate the value of innovative research conducted in Italy," she says, "and to inspire other scientists to pursue their unique paths with confidence and determination."
Conclusion
Ivana Trapani’s receipt of the ERC Starting Grant is a testament to her groundbreaking work in overcoming one of the most significant challenges in gene therapy today. Her innovative approach, leveraging intein technology to expand the capabilities of AAV vectors, could redefine the future of gene therapy, particularly for large-gene disorders. As the NextGeneTx project progresses, it promises to set new standards for safety, efficacy, and adaptability in gene therapy, bringing hope to countless patients affected by genetic diseases.
