26 – 28 September 2025, Freiburg, Germany
Summary report written by the Inborn Error Working Party Junior Committee
From 26 to 28 September 2025, the picturesque city of Freiburg hosted the Inborn Errors Working Party (IEWP) Annual Conference. Under the leadership of Maria Ester Bernardo (Chair), Claire Booth (Secretary), and local organizer Carsten Speckmann, 185 delegates from 25 countries gathered for three dynamic days devoted to stem cell transplantation and gene therapy in inborn errors of immunity (IEI) and metabolism (IEM).
The meeting opened with a keynote by Petter Brodin, who illustrated how systems immunology can unravel the complex cellular interactions shaping human immunity. He highlighted how hormonal and microbial cues and early-life exposures influence immune development and variability across individuals. His talk emphasized that human immunity is shaped by dynamic cell–cell interactions, and therefore controlled perturbation studies are essential.
The following session focused on immune responses in hematopoietic stem cell gene therapy (HSC-GT) for metabolic disorders. Valeria Calbi presented the first reported case of graft failure after HSC-GT for metachromatic leukodystrophy (MLD), exploring possible immune and infectious causes and underscoring the need for predictive biomarkers. Troy Lund followed with a case of X-linked adrenoleukodystrophy (X-ALD) complicated by anti-ALDP antibodies and graft loss, successfully rescued by allogeneic HSCT—highlighting the immune challenges of GT in patients lacking endogenous protein expression.
Gizem Zengin Ersoy shared experience with HSCT in mucolipidosis type II (MLII), showing modest neurological improvement and stable donor chimerism, while Giulia Consiglieri, Ramya Nataraj, and Nathan Jeffreys presented encouraging long-term outcomes from MPS I, IIIA, and II gene therapy trials, demonstrating sustained enzyme activity and clinical benefit.
Pim Pijnappel discussed gene therapy for Pompe disease, introducing LentiCure, a new initiative promoting transparent pricing of lentiviral therapies. Francesca Tucci outlined a forthcoming trial in TCIRG1-related osteopetrosis using UM171-mediated HSPC expansion and improved vectors to enhance engraftment. Finally, Jenna Nunn presented draft EBMT guidelines for infection prophylaxis and immunization after HSC-GT, recommending tailored antimicrobial strategies and immune monitoring to guide safe re-vaccination.
Next, an overview of ongoing and planned IEWP collaborative studies was given. Claire Booth outlined the process for initiating new projects, emphasizing transparency, data sharing, and opportunities for early-career investigators. Rob Chiesa presented data from 746 osteopetrosis transplants across three decades, showing improved survival with modern conditioning but persistent genotype–phenotype effects, particularly poorer outcomes for CLCN7 variants. Emmeline Buddingh reported 72% post-HSCT survival in a recent cohort of STAT1 gain-of-function patients, with improved outcomes linked to ruxolitinib pre-treatment and alemtuzumab conditioning.
Carsten Speckmann summarized the forthcoming IEWP consensus guideline on JAK inhibitor use in JAK/STAT-related IEIs, developed through an international Delphi process and review of 1600 articles. Kanchan Rao gave an update on the MHC class II deficiency study, and Violante Gustuti confirmed the benefit of preemptive HSCT in familial HLH.
The session concluded with Srividya Senthil and Alexandra Laberko presenting early results from the RALD study, showing immune recovery despite graft failures, while Arjan Lankester and Reem Elfeky proposed new studies on SCID and Chediak-Higashi syndrome respectively.
A session on combined immunodeficiencies (CID) provided updates on conditioning strategies, with comparative data presented by Chris Dvorak on busulfan versus treosulfan. Age-specific thresholds were identified, and while very young children may require higher doses, this raises the question of whether delaying HSCT could help mitigate toxicity risks. Su Han Lum compared treosulfan- and busulfan-based conditioning in SCID across large multicenter cohorts. Both regimens achieved similar survival, though busulfan was associated with increased endothelial complications. Dharmagat Bhattarai shared a single-center experience from Nepal, reporting encouraging results of HSCT in five patients with ARPC1B deficiency, despite significant resource constraints.
The session concluded with Luigi Notarangelo, who presented novel insights into IL-7 deficiency. Unlike IL-7 receptor defects, IL-7 deficiency may manifest later in life. Recent work with artificial thymic organoids and TSLP supplementation has demonstrated promising proof-of-concept for promoting T-cell differentiation, opening new avenues for therapy.
During the keynote of the second day, Robert Zeiser presented new insights into the triggers of acute GvHD, focusing on how pathogens and immune pathways interact to cause inflammation in the gut. He showed that JAK1/2 inhibition with ruxolitinib suppresses alloreactive T cells while promoting regulatory T cells, improving survival compared to standard therapy, though outcomes remain poor for intestinal GvHD. Recent work suggests benefit of GLP-2 combined with ruxolitinib in refractory disease. Zeiser also noted similarities between checkpoint inhibitor colitis and aGvHD, with extracorporeal photopheresis showing good efficacy, particularly for colitis. Finally, he presented novel findings on gastric involvement in aGvHD, linking reduced gastrin levels to disease severity and suggesting that gastrin staining on biopsies could guide early diagnosis and management.
The next session turned to advances in gene therapy and genome editing, showcasing the latest translational developments across multiple IEIs. Elizabeth Kang presented updates on all current CGD studies at the NIH, covering both allogeneic HSCT and gene therapy protocols. For X-linked CGD, lentiviral trials using high-dose busulfan have evolved through several iterations, eventually incorporating ustekinumab, rituximab, sirolimus, tocilizumab, and eltrombopag to control inflammation and improve engraftment. A base editing trial has opened, with one patient treated showing successful engraftment of edited cells. For autosomal recessive p47-CGD, lentiviral and prime-editing–based protocols have recently opened. At the NIH, one patient was treated with Prime Medicine’s prime editing product; but the program paused following the company’s withdrawal. Efforts continue in the US and UK to relaunch the trial. Claire Booth introduced an in vivo gene therapy approach for X-CGD (Ensoma EN-374), in which patients receive G-CSF and plerixafor before administration of the in vivo vector, followed by three rounds of mild chemotherapy to enrich for gene-modified (chemo-resistant) cells. The trial is open in the US and under review in the UK.
Sung-Yun Pai summarized viral gene therapy for X-SCID, where patients treated with SIN-γRV did not show insertional oncogenesis, but suboptimal immune reconstitution, whereas the current SIN-LV with low-dose busulfan conditioning resulted in most patients discontinuing immunoglobulin replacement and achieving good immune recovery. Emma Morris presented cutting-edge base editing data in STAT1 gain-of-function and APDS (PIK3CD). Base editing restored normal interferon signaling and T-cell differentiation in STAT1 GOF and corrected aberrant PI3K signaling in APDS. In both patient T cells and HSCs, high editing efficiency was achieved with sustained functional rescue and no off-target effects or engraftment defects observed. Jean-Sébastien Diana introduced the FHL3 gene therapy trial (NCT07736080) for UNC13D deficiency, combining CD34+ and T-cell infusions. He also highlighted ongoing gene therapy efforts for Artemis-SCID (under compassionate use) and IPEX syndrome. Toni Cathomen presented preclinical base editing studies in the jinx mouse model of FHL3, showing correction in both T cells and HSCs with functional rescue. He emphasized that off-target effects are both platform- and cell-type–specific, underscoring the need for tailored validation strategies in genome-editing development. Alessandro Aiuti reported results from the Telethon WAS gene therapy trial (Telethon003). Among 27 treated patients, stable multilineage engraftment, reduced infection rates, and resolution of bleeding were achieved. Market authorization applications have now been submitted to both EMA and FDA. Finally, Arjan Lankester presented the RAG1-SCID gene therapy update, with five patients treated to date, four identified through newborn screening. Notably, all products were manufactured centrally at the LUMC, with two shipped and reinfused at the patients’ home centers.
The first-ever nurses session at the IEWP meeting highlighted the expanding role of nursing in immunology and gene therapy. Susan Farish emphasized the importance of structured long-term follow-up and direct handovers to ensure continuity of care, patient education, and psychosocial support after transplantation. Federico Fraschetta shared insights from the Wiskott–Aldrich gene therapy program at San Raffaele, illustrating the vital role of research nurses in coordinating complex treatment pathways and supporting international families throughout therapy.
The subsequent session on autoimmune diseases opened with Jana Pachlopnik, who presented data on ZNFX1 deficiency, a severe dysregulatory IEI with HLH-like features and poor HSCT outcomes. Rebecca Marsh followed with case illustrations suggesting a genetic basis in some patients with systemic juvenile idiopathic arthritis (sJIA) and discussed HSCT strategies in these cases. Benjamin Fournier reported the Paris experience with HSCT for Still’s disease–associated lung disease, and Juliana Silva presented data on long-term relapse risk after allogeneic transplantation.
The next session focused on EBV-related inborn errors of immunity (IEI) and EBV-driven pathology, beginning with Benjamin Fournier, who outlined the spectrum of chronic active EBV (CAEBV) and emphasized the distinction between common B-cell infection and the rare, severe T- or NK-cell forms. He highlighted the EBER Flow-FISH assay as a rapid and accurate method to identify EBV+ lymphocyte subsets.
Ashish Kumar shared the Cincinnati experience using nivolumab for refractory EBV lymphoproliferative disorders (LPDs), achieving clinical and molecular remission in all seven SEBVTCL patients treated. Jeremy Rubinstein discussed the role of virus-specific T cells (VSTs) in managing EBV complications post-HSCT and SOT, noting that both donor-derived and third-party VSTs are safe and effective, with tabelecleucel now approved in Europe for second-line PTLD. Tobias Feuchtinger presented adoptive T-cell therapy (ACT) as an essential option for severe viral infections after transplantation and underscored the need for controlled studies such as the ongoing TRACE trial.
The subsequent session addressed B-cell reconstitution, providing new insights into the recovery and long-term challenges of humoral immunity following transplantation. Marta Rizzi opened the session by presenting lessons on B cell development derived from IEI. She demonstrated that poor B cell reconstitution following HSCT or Rituximab is often caused by a defect in the BM microenvironment, rather than just the stem cells. Bénédicte Neven discussed Ab deficiency despite normal B cell counts in patients receiving RTX post-HSCT. Her team's analysis revealed a profound depletion of switched memory B cells and antibody secreting cells in patients requiring long-term IgRT, yet no predictive risk factors were identified. Further study is required to determine the underlying mechanism.
Mirjam van der Burg emphasized the importance of BCR repertoire analysis as a measure of reconstitution quality post-HSCT. She noted that while the naïve BCR repertoire achieves full diversity early, the antigen-selected repertoire develops slowly over the first two years. Future research is necessary to study the link between the cellular and secreted antibody repertoires.
Manfred Hönig focused on B cell reconstitution in B+SCID patients after HSCT. His research showed that very low peripheral donor B cell chimerism may be sufficient to achieve B cell function and Ig-independence. He proposed that the proportion of IgM− B cells within the CD27+ subset correlates strongly with B cell function, thus offering a practical marker for routine follow-up post-HSCT.
The second nurses session opened with a compelling case presentation by Helen Braggins and Jinhua Xu Bayford of a 20-year-old patient with chronic granulomatous disease (CGD) suffering from severe infections and inflammatory bowel disease. The discussion highlighted the complexity of treatment decisions—ranging from supportive care to HSCT and gene therapy—and the crucial role of nurses in supporting shared decision-making, educating families, and ensuring patient-centered care.
Evey Howley then discussed thymus transplantation in children with conditions such as 22q11 microdeletion or CHARGE syndrome. She emphasized the importance of multidisciplinary coordination and introduced a new clinical summary form designed to improve communication and ease the burden on families while maintaining high-quality care. Marina Ben Izhak concluded the session with insights from HSCT in osteopetrosis, reviewing outcomes from 66 patients. She underscored the importance of close monitoring, early complication management, and multidisciplinary teamwork, while highlighting the essential contribution of nurses in patient education, emotional support, and post-discharge care.
Subsequently, Ruben Van Paemel presented a striking case in which familial HLH type 3 was unmasked following chronic disseminated rubella infection post-MMR vaccination. Francesco Cinetto discussed granulomatous lymphocytic interstitial lung disease (GLILD) in CVID, emphasizing diagnostic difficulties and the need for personalized therapy using corticosteroids or rituximab. Klaus Warnatz focused on gastrointestinal manifestations, including enteropathy and hepatopathy, which are associated with increased mortality. He discussed the possible role of chronic norovirus infection and highlighted therapeutic approaches ranging from budesonide and biologics to HSCT in select cases.
Helen Leavis presented work on biomarker discovery in complex CVID, identifying molecules such as Gal9, CXCL10, IL6, and IL10 to better stratify disease severity. She also announced the launch of a new ESID registry cohort on CVID enteropathy. Luiza Campos followed with data from the UK Intrepid genome sequencing initiative, demonstrating how Human Phenotype Ontology (HPO) terms enable standardized data collection and integration of longitudinal clinical information.
Finally, Emma Morris provided an update on HSCT in CVID, noting poorer outcomes than in other IEIs. She announced a retrospective study on HSCT in CVID and invited clinicians to present challenging cases to the international MDT she coordinates.
In the next session, Miriam Erlacher discussed the overlap between immunodeficiency and bone marrow failure, illustrated by a case of hereditary folate malabsorption presenting with cytopenias.
Marcin Wlodarski presented updates on SAMD9/9L syndromes, emphasizing the neurological manifestations and the variability of genotype–phenotype correlations. He introduced an online mutation atlas hosted by St. Jude and highlighted revertant mechanisms such as UPD that can lead to spontaneous clinical improvement.
Brigitte Strahm discussed the spectrum of GATA2 deficiency: from bone marrow failure and immunodeficiency to MDS and leukemia. She highlighted the variability of phenotypes even in the same families, which makes counseling challenging. An online atlas with mutations is now available at the St Jude homepage. GATA2 deficiency should always be considered in adolescents with MDS with monosomy 7. However, there is no correlation between mutation and HSCT outcome.
Federica Barzaghi described the “chameleon-like” nature of ADA2 deficiency, showing its overlap with bone marrow failure and inflammatory conditions, as demonstrated by the beneficial effect of TNFα inhibition in stroke prevention. She concluded with two illustrative cases of successful HSCT in affected twins.
Luca Vinci closed the session with two unusual cases of SAP deficiency presenting as severe aplastic anemia, highlighting the importance of maintaining diagnostic awareness even for well-known diseases.
The final session focused on expanding transplant indications and improving conditioning approaches. Paul Szabolcs presented a case of HSCT in PLAID syndrome, with encouraging initial outcomes despite later complications. Catharina Schütz shared sobering data on HSCT in NFKB2 deficiency, where post-transplant neurological complications and persistent anti-interferon antibodies may contribute to poor survival.
Helena Lichtenfeld reviewed the spectrum from chronic active EBV infection to EBV+ T-cell lymphoma with HLH, emphasizing the importance of precise disease definition and the poor prognosis once HLH develops. Sujal Ghosh concluded the scientific program with model-based fludarabine dosing in infants, showing promising results in reducing toxicity.
Beyond the scientific program, our recently instated junior committee—composed of many former IEWP Spring School participants—organized a social program, including a photo challenge, Friday evening drinks at Café Jos Fritz, and an early Saturday morning run with a record 23 participants. That evening, the conference dinner at Dattler Schlossbergrestaurant offered a beautiful view of Freiburg and a special coming together of old and new friends. The younger generation was inspired by the dedication and experience of long-standing IEWP members who have shaped the field over many decades.
At the closing session, Tayfun Güngör announced that the next IEWP Annual Meeting will be held in Zurich from 25–27 September 2026, at the new Children’s Hospital and Science Tower near Lake Zurich. The IEWP Annual Meeting once again proved to be a highlight of the year—a big thanks to the hosts from Freiburg - we are already looking forward to next year.