From Wiskott–Aldrich Syndrome to a new model for gene therapies

Rare and ultra-rare genetic diseases pose profound scientific, human and economic challenges. The development of gene therapy for Wiskott–Aldrich syndrome (WAS) is a clear example of this complexity.

The treatments available for these conditions are often ineffective, insufficient, or unsuitable for many patients. Research advances slowly, grounded in scientific knowledge that is still emerging, while technological innovation evolves at a much faster pace. The very small number of patients further complicates the design of clinical trials and demands substantial investment to sustain research, manufacturing, regulatory approval and long-term follow-up.

This is the story of Fondazione Telethon’s long-standing commitment — a journey that began with the conviction to invest in a therapeutic approach that was still pioneering, and that has now led to the commercialisation of an approved gene therapy. A journey made possible through synergy and collaboration between academic researchers, pharmaceutical partners, funders and donors, patient associations and regulatory authorities.

On 14 November, the CHMP of the European Medicines Agency (EMA) issued a positive opinion for the commercial authorisation of ex vivo gene therapy for Wiskott–Aldrich syndrome (WAS), a rare and severe primary immunodeficiency. Shortly after - on 10 December - the US Food and Drug Administration (FDA) also granted approval for Waskyra (etuvetidigene autotemcel) for the treatment of WAS in the United States

WAS is an X-linked genetic disorder that affects almost exclusively boys, causing profound immunodeficiency, bleeding complications due to low and mostly dysfunctional platelets, recurrent infections, and an increased risk of autoimmunity.

Researchers and clinicians at SR-TIGET (San Raffaele–Telethon Institute for Gene Therapy) began working on gene therapy for WAS in the 1990s for several key reasons. First, it was a well-characterised disease, supported by a solid and extensive body of research. The existing treatment — haematopoietic stem cell transplantation — is effective and well established, yet not suitable for all patients: some lack a compatible donor, while others may not tolerate the intensive conditioning regimens required.

For these patients, gene therapy offers a crucial alternative.

Unlike transplantation, no immunosuppression is required, as the corrected cells originate from the patient and therefore pose no compatibility issues. Moreover, WAS presents a unique selective advantage: once reinfused, corrected cells naturally outcompete defective ones. This phenomenon had already been observed in earlier studies on ADA-SCID, another rare immunodeficiency and the first disease for which a Fondazione Telethon-developed gene therapy was approved.

Developing a gene therapy for WAS proved significantly more challenging than the earlier experience with ADA-SCID, due to several molecular and clinical specificities. In particular:

To address these intrinsic challenges, researchers drew on pioneering work from the 1990s by Luigi Naldini, Director of SR-TIGET, on lentiviral vectors derived from HIV. Their high infectivity and efficient gene-transfer capacity allow for a safe and effective correction, enabling modification of over 90% of target cells.

Once reinfused into patients, these corrected haematopoietic stem cells can regenerate the immune system, produce functional platelets, and generate competent immune cells.

From the first clinical studies to the recent positive opinion from the CHMP (EMA) and the approval of FDA, fifteen years have passed. The full journey, however, spans over thirty-five years, demanding substantial resources in terms of expertise, technologies, collaborations, and funding.

Among the many milestones, two moments stand out as truly decisive — both in achieving an effective therapy and in shaping the strategic model that Fondazione Telethon would ultimately adopt.

The first breakthrough came when the team observed the engraftment of the corrected cells. “When we saw the corrected cells engraft, we began to hope” recalls Alessandro Aiuti, Deputy Director of SR-TIGET. “Those corrected cells continued to expand over time, leading to the reconstitution of the immune system, an increase in platelet counts, and, consequently, early clinical improvements in the first treated patients.”

A second turning point concerned the sustainability of the programme. The development of the WAS gene therapy had initially been taken on by pharmaceutical companies — first GSK (2013–2018), followed by Orchard Therapeutics (2018–2023) — which had the specialised capabilities required to move a therapy from clinical research to commercialisation.
 The shared goal was clear: bringing the therapy to market.

However, in 2023, Orchard Therapeutics decided to discontinue the programme and prioritise other therapeutic areas. This decision had profound implications. As Aiuti recounts: “It was an extremely difficult moment. We asked ourselves: how do we tell the patients on the waiting list? How do we tell the families of those who have already received the treatment and need ongoing follow-up? How do we tell the researchers who have invested their passion, time, and energy?”

This turning point opened a completely new path — one that had never been taken before. In a bold and unprecedented move, Fondazione Telethon assumed responsibility for bringing the therapy to market, investing in internal capabilities and resources to secure its registration, reimbursement, and regulatory approval both in Europe and the United States.
For the first time, a non-profit organisation took on a role traditionally reserved for industry — not only in financial terms, but by navigating a regulatory and commercialisation process unfamiliar to the academic world.

Rare and ultra-rare diseases, by definition, involve very small patient populations, which poses inherent challenges for clinical research. Ethical considerations often make it necessary to use single-arm study designs rather than randomised, placebo-controlled trials. This inevitably raises questions about the statistical significance and robustness of the resulting data.

For the Wiskott–Aldrich Syndrome (WAS) gene therapy, the CHMP’s positive opinion and FDA approval is grounded in the strength of a clinical development programme involving 27 patients in total, led by Francesca Ferrua, paediatric haematologist at the San Raffaele Paediatric Immunohaematology Unit in Milan. Over time, treated patients showed a marked and sustained reduction in both severe infections and bleeding episodes — the two primary clinical endpoints.

Beyond these main outcomes, a wide range of biological and clinical parameters — including engraftment and long-term persistence of corrected cells, and multiple immunological and haematological markers — all produced consistent and positive results. This convergence of evidence confirms that the therapeutic effect is not random, strengthening the clinical significance of the primary findings. Moreover, the long duration of follow-up provides essential insight into the therapy’s benefit–risk balance and confirms its durability over time.

As Alessandro Aiuti notes, “The robustness of the data, the concordance across all parameters, and the persistence of the effect — given that the therapy is intended to last for a lifetime — are the key elements that validate both the clinical study and the quality of the therapy.”

As with all scientific progress, today’s advances stand on the foundations laid by decades of earlier work. The experience gained from ADA-SCID and Wiskott–Aldrich Syndrome (WAS) has made it possible to identify several core principles that underpin successful gene therapy. These include the use of lentiviral vectors — originating from Luigi Naldini’s pioneering work in the 1990s — the ability to achieve effective correction even with reduced-intensity conditioning when corrected cells have a selective advantage, and robust long-term evidence showing that corrected cells can persist and self-renew for more than fifteen years. Crucially, the engineering process does not alter the fundamental properties of haematopoietic stem cells, which retain their ability to regenerate all blood and immune cell lineages.

Building on these lessons, researchers have refined the next generation of treatments by applying the manufacturing processes developed for WAS to other conditions, such as lysosomal storage diseases, including mucopolysaccharidosis type I. Work on this third disease has expanded knowledge on vector manufacturing, quality control, and the correction of pathological defects across multiple organs, including the skeleton and the central nervous system.

As Alessandro Aiuti explains, “The idea now is to build a technological platform that can serve as a model. By using the same type of viral vector, the same production system, and the same preclinical and clinical approach, the only difference between these therapies would be the therapeutic gene itself — a strategy that could significantly reduce both time and cost.”

Gene therapy is inherently complex: it requires patients to donate their own stem cells — something that is not always possible — and to undergo prolonged, continuous follow-up to assess long-term safety. Yet despite these challenges, it represents an additional and often transformative opportunity for patients, making it essential to continue investing in its potential.

The field is also evolving rapidly and faces a race against time: while drug development progresses slowly and in well-defined stages, technological innovation moves much faster. As a result, we now have robust therapies built on solid platforms — such as lentiviral vectors — alongside newer approaches still under investigation, including mRNA-based gene therapies and gene editing. The latter, although supported by more limited clinical experience to date, enables the insertion of a healthy gene into its precise genomic location, offering particular promise for diseases that require highly regulated gene expression.

Taken together, these techniques — and the scientific advances behind them — highlight the considerable potential of gene therapy and the value of collaboration between research institutions, non-profit organisations, and industry.

And the future? To have a toolbox of different therapeutic strategies, each applied according to the specific disease and clinical objective, while recognising the time, rigour, and complexity that scientific progress demands.