The therapeutic alliance between a patient and their physician — or the researcher studying their disease — is vital across all areas of human health. But in the field of rare diseases, where the diagnostic process is often long and complex, definitive treatments are lacking, and available therapies are largely experimental, this alliance becomes indispensable. Clear communication and the active involvement of patients and their families in therapeutic decision-making are not only an ethical obligation but also a critical driver of research progress.
The Convention of Patients Associations, held during the 22nd Telethon Scientific Convention in Rimini, Italy, provided a valuable opportunity for dialogue between scientists engaged in cutting-edge research on rare and ultrarare hereditary diseases and the patient associations that represent affected individuals and their families. Organized by the Telethon Foundation — an Italian nonprofit dedicated to funding and advancing research on rare genetic diseases — the event aimed to facilitate the exchange of knowledge and perspectives along the continuum from laboratory research to clinical application.
“People living with rare diseases and their families place great trust in our work,” said Alessandro Aiuti, MD, PhD, head of the Pediatric Immunohematology Unit at IRCCS San Raffaele Hospital and deputy director of clinical research at the San Raffaele Telethon Institute for Gene Therapy (San Raffaele-TIGET) in Milan, Italy. “At the same time, they — and we — ask the inevitable question: Is the path we are following the right one? Will it lead to a cure for my disease?”
Overcoming Obstacles
Even for those conducting the research, many uncertainties remain. “At present, not all hereditary rare diseases are potentially treatable with gene therapy,” explained Aiuti. “In choosing which conditions to target, we prioritize those for which we can apply the technologies we already have.”
“One major obstacle,” he continued, “is the challenge of reaching specific tissues and organs. In vitro, all cells are accessible to the viral vectors we use to deliver corrective genes into the nucleus. But in vivo, it is much more difficult to guide the genes precisely to the intended targets without affecting other cells.”
Vector capacity also presents a significant technical limitation. “Some genes are too large to be packaged into viral vectors,” noted Alberto Auricchio, MD, professor of medical genetics at the University of Naples Federico II and scientific director of the Telethon Institute of Genetics and Medicine (TIGEM) in Naples, Italy. “Approximately 1200 human genes exceed the size limit for viral delivery, and many of these are involved in hereditary diseases. The good news is that we’re making progress. At TIGEM, we recently developed a technique that involves splitting an oversized corrective gene into two parts. Each half is delivered into the target cell using a separate vector. Once inside the nucleus, the two segments reassemble. We’ve used this approach to create an experimental treatment for a hereditary degenerative eye disorder — Usher syndrome type 1B — which is now in clinical trials.”
Another barrier to successful gene therapy is immunogenicity — the risk of triggering an immune response to the viral vector itself. “And not just the vector,” added Nicola Brunetti-Pierri, MD, professor of pediatrics at the University of Naples Federico II and coordinator of TIGEM’s Molecular Therapy research plan. “Transduced cells — those that have received the corrective gene — may express viral proteins on their surface. The immune system can then misidentify them as infected cells and mount an attack. It’s essential to clearly communicate both the potential benefits and the risks of failure to patients and their families during experimental trials.”
Therapeutic Toolbox
Classical gene therapy is no longer the only approach available for treating hereditary rare diseases. “The past decade has seen a proliferation of new technologies,” said Aiuti. “For example, gene editing enables us to insert a functional copy of a gene at a precise genomic location or even to correct individual base-pair mutations in defective genes. Epigenetic editing allows us to silence a gene using proteins that bind to DNA without altering its sequence. And mRNA [messenger RNA]-based therapies can prompt cells to temporarily produce specific proteins. All of these are promising strategies that we are pursuing in parallel with traditional gene therapy research.”
Role of Patient Associations
In this evolving therapeutic landscape, patient associations play a critical role in maintaining open channels of communication and collaboration with the research community. These organizations help identify urgent unmet needs, shape research agendas, and ensure the dissemination of accurate, up-to-date information to affected families.
“Sometimes, research breakthroughs are reported with excessive enthusiasm, which can foster unrealistic expectations,” noted Simona Borroni, president of the Dravet Syndrome European Federation, Paris, an umbrella organization that brings together national patient associations across Europe to support individuals affected by Dravet syndrome and promote research, awareness, and advocacy efforts. “Families must also be equipped to make informed decisions about participating in clinical trials for new therapies. For example, a phase 3 clinical trial has recently been approved for a drug that may potentially modify the natural course of Dravet syndrome. The trial has already begun in the United States and is expected to launch in Europe and Italy next year. As an association, our role is to help families understand all aspects of the trial — from the invasive nature of the drug administration procedure to the existence of a control group that will not receive the treatment.”
Collaboration between associations and researchers is a two-way relationship: Patient organizations help fund scientific projects and advocate for the importance of basic research, which is essential for understanding disease mechanisms and optimizing the use of available therapies. “It’s also important to report failures,” Borroni emphasized. “Failures help eliminate dead ends and guide the research process more effectively, avoiding unnecessary duplication and wasted resources. Our community would benefit if scientific journals published failures alongside successes.”
The Time Factor
While ongoing research offers hope, time remains a critical factor for patients and their families. “Bringing a new gene therapy to market involves a series of essential steps to ensure patient safety,” explained Aiuti. “At the same time, people living with these conditions urgently need access to promising therapies — especially since many are effective only within a specific therapeutic window.”
To address this challenge, the Telethon Foundation has initiated discussions with regulatory agencies, including the European Medicines Agency and the US Food and Drug Administration, to shorten approval timelines for new drugs. “At San Raffaele-TIGET, we’ve developed several therapies that follow a common protocol,” Aiuti said. “We collect the patient’s hematopoietic stem cells, modify them in the laboratory by inserting the corrective gene using an HIV-derived viral vector, and then reinfuse the cells. The only variation from one therapy to another is the specific gene being inserted. By using this standardized platform, we can work in parallel to develop multiple therapies for certain metabolic diseases, eliminating unnecessary steps and saving both time and resources.”
There are also mechanisms for accessing treatments before they receive formal regulatory approval. “The most structured path is participation in a clinical trial,” Aiuti noted. “For patients who do not meet the criteria, compassionate use may be an option under specific conditions.”
This story was translated from Univadis Italy using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.