Reacción a "Gene therapy is effective long-term in children with a serious rare disease"

Study analysis: 62 patients with ADA-SCID [severe combined immunodeficiency due to ADA enzyme deficiency] treated between 2012–2019 in the US and UK with a mean follow-up of 7.5 years (474 patient-years).

Main results:

• Efficacy: 100% overall survival and 95% event-free survival (59/62) in the long term. (‘Event’ = death, restart of enzyme replacement therapy [ERT], rescue with allogeneic haematopoietic stem cell transplantation [HSCT], or repeat gene therapy).
• Safety: no leukoproliferation or dominant clonality; polyclonal integration up to 120 months. No competent lentivirus. Mild/moderate unrelated late adverse events.

Strengths:

• Large, multicentre cohort for an ultra-rare disease, with very long follow-up (≥5 years all; mean 7.5 years).
• Consistency between fresh vs. cryopreserved product and between cell sources (bone marrow vs. mobilised peripheral blood), indicating broad operability.
• Reassuring genotoxic profile compared to historical first-generation γ-retroviral vectors, where the presence of insertion-associated T-cell leukaemias near the LMO2 oncogene was documented.

Weaknesses of the study and aspects to be interpreted with caution:

• Non-randomised design and no comparison control group (e.g. allogeneic HSCT with less harmful conditioning). Possible selection bias (US with neonatal screening; UK without screening at the time), although this may rather enrich the interpretation.
• Early failure in 3/62 (≈5%) requiring ERT/HSCT; no clear predictors reported. However, this is a very low failure rate, so it can be considered a first-line treatment.
• Heterogeneity in cell source and formulation which, although pragmatic, complicates fine causal inference (e.g. higher CD34+ doses in the UK).
• Rare late events: although not observed, the number of patients is still too limited to rule out very rare genotoxicity risks beyond 10–15 years.
• Translation/commercialisation: the study itself highlights limited commercial viability (costs, population size) and the need for alternative access models.

In how many immunodeficiencies are there successful trials?

• If we understand “successful” to mean sustained clinical and immune correction with modern vectors and no serious signs of genotoxicity in the medium term, at least four IEIs [innate immune errors] with solid results can be considered today:
• ADA-SCID: this study confirms sustained long-term efficacy and safety with LV-SIN (OS 100%, EFS 95%).
• X-SCID (IL2RG): trials with optimised lentivirus show rapid and robust T-cell reconstitution and 100% survival in paediatric series; the evidence has matured since 2019 and remains positive.
• Artemis deficiency SCID (DCLRE1C): convincing immune correction and low toxicity; extended follow-up maintains favourable signs.
• Wiskott-Aldrich syndrome (WAS): prolonged follow-up confirms sustained clinical benefit.

What it means for practice: for ADA-SCID, this gene therapy is positioned as a potentially curative therapy with a lower busulfan burden than haematopoietic progenitor transplantation, avoiding alloreactivity and with robust functional evidence.

It should be noted that the first trials were conducted in the US (ADA-SCID) and France (X-SCID) and both were successful, although the retroviral vectors used caused several problems (T-cell leukaemia). Much safer vectors, based on lentiviruses, are currently used. However, the only treatment approved by the EMA (Strimvelis) uses these older types of vectors.

It is important to note that the latest series published for ADA-SCID, X-SCID, Artemis-SCID and WAS show no significant risks and should be considered safe and reliable therapies.

Unfortunately, there is no centre in Spain that administers these treatments, and when they are needed because there is no suitable donor for a bone marrow transplant, patients have to be sent to the United Kingdom or Italy. This is particularly unfortunate given that this is a state policy and that it should be the responsibility of the Ministry of Health to implement it through an appropriate hospital unit or at the Carlos III Health Institute. In fact, there is a group actively working at CIEMAT, led by Dr Bueren, who not only has extensive experience in gene therapy research, but has also contributed to a recent article published in NEJM this year.

The implementation of gene therapy and making it accessible to our paediatric patients, with the essential addition of including these diseases in the heel prick test (neonatal screening), which is something that is only done in Catalan children, should be priorities throughout Spain, as already stated in the National Strategy on Rare Diseases.