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1. Infecties van de urinewegen

Author

Geerlings, S. E., Boelens, J., Hoepelman, A. I. M., Hoepelman, prof. dr. A.I.M., editor, Kroes, prof. dr. A.C.M., editor, Lagrou, prof. dr. K., editor, Van der Hilst, prof. dr. J.C.H., editor, Wertheim, prof. dr. H.F.L., editor, Bonten, prof. dr. M.J.M., editor, van Hellemond, dr. J.J., editor, Vlieghe, prof. dr. E.R.J., editor, and van Vugt, prof. dr. M., editor

Published
2024
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3. Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation

Author

Uppugunduri, C. R. S., Huezo-Diaz Curtis, P., Nava, T., Rezgui, M. A., Mlakar, V., Mlakar, S. Jurkovic, Waespe, N., Théoret, Y., Gumy-Pause, F., Bernard, F., Chalandon, Y., Boelens, J. J., Bredius, R. G. M., Dalle, J. H., Nath, C., Corbacioglu, S., Peters, C., Bader, P., Shaw, P., Bittencourt, H., Krajinovic, M., and Ansari, M.

Published
2022
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6. Pharmacotherapy in Pediatric Hematopoietic Cell Transplantation

Author

Admiraal, R., Boelens, J. J., Barrett, James E., Editor-in-Chief, Flockerzi, Veit, Editorial Board Member, Frohman, Michael A., Editorial Board Member, Geppetti, Pierangelo, Editorial Board Member, Hofmann, Franz B., Editorial Board Member, Michel, Martin C., Editorial Board Member, Page, Clive P., Editorial Board Member, Wang, KeWei, Editorial Board Member, Kiess, Wieland, editor, Schwab, Matthias, editor, and van den Anker, Johannes, editor

Published
2020
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8. The effects of topical antibiotics on eradication and acquisition of third-generation cephalosporin and carbapenem-resistant Gram-negative bacteria in ICU patients; a post hoc analysis from a multicentre cluster-randomized trial

Author

Cooper, B.S., Coll, P., Lopez-Contreras, J., Mancebo, J., Wise, M.P., Morgan, M.P.G., Depuydt, P., Boelens, J., Dugernier, T., Verbelen, V., Jorens, P.G., Verbrugghe, W., Malhotra-Kumar, S., Damas, P., Meex, C., Leleu, K., van den Abeele, A.M., Esteves, F., de Matos, A.F.G.P., Torres, A., Méndez, S.F., Gomez, A.V., Tomic, V., Sifrer, F., Tello, E.V., Ramos, J.R., Aragao, I., Santos, C., Sperning, R.H.M., Coppadoro, P., Nardi, G., Plantinga, N.L., Wittekamp, B.H.J., Brun-Buisson, C., and Bonten, M.J.M.

Published
2020
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10. Corrigendum: Therapeutic drug monitoring of anti-thymocyte globulin in allogeneic stem cell transplantation: proof of concept (Front. Pharmacol., (2022), 13, (828094), 10.3389/fphar.2022.828094)

Author

Arts-assistenten Kinderen, CTI, Bureau Onderzoek, SCT patientenzorg, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, CTI Research, Cancer, Meesters-Ensing, J. I., Admiraal, R., Ebskamp, L., Lacna, A., Boelens, J. J., Lindemans, C. A., Nierkens, S., Arts-assistenten Kinderen, CTI, Bureau Onderzoek, SCT patientenzorg, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, CTI Research, Cancer, Meesters-Ensing, J. I., Admiraal, R., Ebskamp, L., Lacna, A., Boelens, J. J., Lindemans, C. A., and Nierkens, S.

Published
2024

14. Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study

Author

Huygens, S., Dunbar, A., Buil, J.B., Klaassen, C.H.W., Verweij, P.E., Dijk, K van, Jonge, N. de, Janssen, J, Velden, W.J.F.M. van der, Biemond, B.J., Bart, A., Bruns, A.H.W., Haas, P.A., Demandt, A.M.P., Oudhuis, G., Borne, P. von dem, Beek, M.T. van der, Klein, S.K., Godschalk, P., Span, L.F.R., Postma, D.F., Kampinga, G.A., Maertens, J., Lagrou, K., Mercier, T., Moors, I., Boelens, J. Jan, Selleslag, D., Reynders, M., Zandijk, W., Doorduijn, J.K., Cornelissen, J.J., Schauwvlieghe, A., Rijnders, B.J.A., Huygens, S., Dunbar, A., Buil, J.B., Klaassen, C.H.W., Verweij, P.E., Dijk, K van, Jonge, N. de, Janssen, J, Velden, W.J.F.M. van der, Biemond, B.J., Bart, A., Bruns, A.H.W., Haas, P.A., Demandt, A.M.P., Oudhuis, G., Borne, P. von dem, Beek, M.T. van der, Klein, S.K., Godschalk, P., Span, L.F.R., Postma, D.F., Kampinga, G.A., Maertens, J., Lagrou, K., Mercier, T., Moors, I., Boelens, J. Jan, Selleslag, D., Reynders, M., Zandijk, W., Doorduijn, J.K., Cornelissen, J.J., Schauwvlieghe, A., and Rijnders, B.J.A.

Abstract

Item does not contain fulltext, BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Published
2023

18. CRISPR-Cas9 Editing of the HBG1 and HBGZ Promoters to Treat Sickle Cell Disease.

Author

Sharma, A., Boelens, J·-J·, Cancio, M., Hankins, J. S., Bhad, P., Azizy, M., Lewandowski, A., Zhao, X., Chitnis, S., Peddinti, R., Zheng, Y., Kapoor, N., Ciceri, F., Maclachlan, T., Yang, Y., Liu, Y., Yuan, J., Naumann, U., Yu, V. W. C., and Stevenson, S. C.

Subjects
*SICKLE cell anemia, *CRISPRS, *FETAL hemoglobin, *ERYTHROCYTES
Abstract

BACKGROUND Sickle cell disease is caused by a defect in the 0-globin subunit ofadult hemoglobin. Sickle hemoglobin polymerizes under hypoxic conditions, producing deformed red cells that hemolyze and cause vaso-occlusion that results in progressive organ dam age and early death. Elevated fetal hemoglobin levels in red cells protect against complications of sickle cell disease. OT(2923, a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-edited CD34+ hematopoietic stem- and progenitor-cell (HSPC) product, has a targeted disruption of the HBG1 and HBG2 (y-globin) gene promoters that increases fetal hemoglobin expression in red-cell progeny. METHODS We performed a tiling CRISPR-Cas9 screen of the HBG1 and HBGZ promoters by electroporating CD34+ cells obtained from healthy donors with Cas9 complexed with one of72 guide RNAs, and we assessed the fraction offetal hemoglobin-immune-staining erythroblasts (F cells) in erythroid-differentiated progeny. The gRNA resulting in the highest level of F cells (gRNA-68) was selected for clinical development. We enrolled participants with severe sickle cell disease in a multicenter, phase 1-2 clinical study to assess the safety and adverse-effect profile of OTQ923. RESULTS In preclinical experiments, CD34+ HSPCs (obtained from healthy donors and persons with sickle cell disease) edited with CRISPR:Cas9 and gRNA-68 had sustained on-target editing with no off=target mutations and produced high levels of fetal hemoglobin after in vitro differentiation or xenotransplantation into immunodeficient mice. In the study, three participants received autologous OTQ923 after myeloablative conditioning and were followed for 6 to 18 months. At the end of the follow-up period, all the participants had engraftment and stable induction of fetal hemoglobin (fetal hemoglobin as a percentage oftotal hemoglobin, 19.0 to 26.8°/0), with fetal hemoglobin broadly distributed in red cells (F cells as a percentage of red cells, 69.7 to 87.8%). Manifestations of sickle cell disease decreased during the follow-up period. CONCLUSIONS CRISPR-Casg disruption of the HBG1 and HBG2 gene promoters was an effective strategy for induction of fetal hemoglobin. Infusion of autologous OTQ923 into three participants with severe sickle cell disease resulted in sustained induction of red-cell fetal hemoglobin and clinical improvement in disease severity. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT0444390Z) [ABSTRACT FROM AUTHOR]

Published
2023
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23. Exposure to intravenous posaconazole in critically ill patients with influenza: A pharmacokinetic analysis of the POSA-FLU study

Author

Daele, R. Van, Wauters, J., Dreesen, E., Boelens, J. Jan, Nulens, E., Lormans, P., Vanderbeke, L., Jacobs, Cato, Rijnders, B., Verweij, P.E., Bruggemann, R.J.M., Spriet, I., Daele, R. Van, Wauters, J., Dreesen, E., Boelens, J. Jan, Nulens, E., Lormans, P., Vanderbeke, L., Jacobs, Cato, Rijnders, B., Verweij, P.E., Bruggemann, R.J.M., and Spriet, I.

Abstract

Item does not contain fulltext, BACKGROUND: Data on posaconazole in the critically ill are scarce. In the POSA-FLU study, we examined the prevention of influenza-associated pulmonary aspergillosis with posaconazole in this population. METHODS: In this observational sub-study, we performed a pharmacokinetic analysis, including protein binding and target attainment (TA). Blood samples were collected over a 24 h-dosing interval on both an early (Day 2 or 3) and a later (≥Day 4) treatment day. RESULTS: Target attainment was shown for AUC(0-24) and C(min) prophylaxis but not for C(min) treatment. Moreover, a saturable protein binding with a significant, positive relationship between albumin concentrations and the maximum binding capacity was observed. CONCLUSIONS: Our analysis indicates that posaconazole may be a suitable drug to further investigate for prophylaxis, as TA for prophylaxis was reached. Exposure targets for treatment were insufficiently attained in this population.

Published
2022

24. Therapeutic Drug Monitoring of Anti-Thymocyte Globulin in Allogeneic Stem Cell Transplantation: Proof of Concept

Author

Arts-assistenten Kinderen, Bureau Onderzoek, CTI Nierkens, SCT patientenzorg, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, CDL Patiëntenzorg MI, CTI Research, Cancer, Meesters-Ensing, J I, Admiraal, R, Ebskamp, L, Lacna, A, Boelens, J J, Lindemans, C A, Nierkens, S, Arts-assistenten Kinderen, Bureau Onderzoek, CTI Nierkens, SCT patientenzorg, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, CDL Patiëntenzorg MI, CTI Research, Cancer, Meesters-Ensing, J I, Admiraal, R, Ebskamp, L, Lacna, A, Boelens, J J, Lindemans, C A, and Nierkens, S

Published
2022

25. B-cell depletion abrogates immune mediated cytopenia and rejection of cord blood transplantation in Hurler syndrome

Author

Metabole ziekten patientenzorg, Child Health, Infection & Immunity, SCT patientenzorg, Regenerative Medicine and Stem Cells, Nataraj, R., Hiwarkar, P., Bonney, D., Campbell, H., Jones, S., Deambrosis, D., Evans, P., Poulton, K., van Hasselt, P. M., Bierings, Mb, Boelens, J. J., Lindemans, C. A., Wynn, R., Metabole ziekten patientenzorg, Child Health, Infection & Immunity, SCT patientenzorg, Regenerative Medicine and Stem Cells, Nataraj, R., Hiwarkar, P., Bonney, D., Campbell, H., Jones, S., Deambrosis, D., Evans, P., Poulton, K., van Hasselt, P. M., Bierings, Mb, Boelens, J. J., Lindemans, C. A., and Wynn, R.

Published
2022

27. WS13.05 Mapping and tackling diversity in antibiotic resistance of sputum isolates in cystic fibrosis

Author

Van den Bossche, S., primary, Abatih, E., additional, Grassi, L., additional, De Broe, E., additional, Rigole, P., additional, Cools, P., additional, Versmessen, N., additional, Boelens, J., additional, Van Caenegem, J., additional, Verhasselt, B., additional, Van deWeygaerde, Y., additional, Van Braeckel, E., additional, Coeyne, T., additional, and Crabbé, A., additional

Published
2022
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28. P1344: METHODOLOGY OF AN INTERNATIONAL MULTI-CENTER RETROSPECTIVE REVIEW OF TRANSPLANT-ASSOCIATED THROMBOTIC MICROANGIOPATHY (TA-TMA) BY THE TA-TMA WORKING GROUP

Author

Ho, V., primary, Duarte, R. F., additional, Boelens, J.-J., additional, Cairo, M. S., additional, Champlin, R. E., additional, Giralt, S., additional, Hamadani, M., additional, Higham, C. S., additional, Jerkins, J. H., additional, Laurence, J., additional, Mayer, S., additional, Nakamura, R., additional, Penack, O., additional, Perales, M.-A., additional, Rondón, G., additional, Scordo, M., additional, Hingorani, S., additional, and Vasu, S., additional

Published
2022
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31. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial

Author

De Waele, Jan J., Carrette, S., Carlier, M., Stove, V., Boelens, J., Claeys, G., and Leroux-Roels, I.

Subjects
Care and treatment, Research, Health aspects, Meropenem -- Research -- Health aspects
Abstract

Author(s): Jan J. De Waele [sup.1], S. Carrette [sup.1], M. Carlier [sup.2], V. Stove [sup.2], J. Boelens [sup.2], G. Claeys [sup.2], I. Leroux-Roels [sup.2], E. Hoste [sup.1], P. Depuydt [sup.1], [...], Purpose There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment. Methods This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100 % fT.sub.>4MIC [percentage of time during a dosing interval that the free (f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100 % fT.sub.>4MIC and 100 % fT.sub.>MIC at 72 h. Results Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100 % fT.sub.>4MIC was achieved in 21 % of the PTZ patients and in none of the MEM patients; 100 % fT.sub.>MIC was achieved in 71 % of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100 % fT.sub.>4MIC and 100 % fT.sub.>MIC were higher in the intervention group: 58 vs. 16 %, p = 0.007 and 95 vs. 68 %, p = 0.045, respectively. Conclusions Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.

Published
2014
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36. Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation

Author

Uppugunduri, C. R. S., primary, Huezo-Diaz Curtis, P., additional, Nava, T., additional, Rezgui, M. A., additional, Mlakar, V., additional, Mlakar, S. Jurkovic, additional, Waespe, N., additional, Théoret, Y., additional, Gumy-Pause, F., additional, Bernard, F., additional, Chalandon, Y., additional, Boelens, J. J., additional, Bredius, R. G. M., additional, Dalle, J. H., additional, Nath, C., additional, Corbacioglu, S., additional, Peters, C., additional, Bader, P., additional, Shaw, P., additional, Bittencourt, H., additional, Krajinovic, M., additional, and Ansari, M., additional

Published
2021
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38. B-cell depletion abrogates immune mediated cytopenia and rejection of cord blood transplantation in Hurler syndrome

Author

Nataraj, R., primary, Hiwarkar, P., additional, Bonney, D., additional, Campbell, H., additional, Jones, S., additional, Deambrosis, D., additional, Evans, P., additional, Poulton, K., additional, van Hasselt, P. M., additional, Bierings, MB., additional, Boelens, J. J., additional, Lindemans, C. A., additional, and Wynn, R., additional

Published
2021
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41. Antimicrobial prescription in severe COVID-19 and CAP: a matched case-control study

Author

Fierens, J., De Bus, L., Colpaert, K., Boelens, J., Gadeyne, B., Decruyenaere, J., Van Braeckel, E., and Depuydt, P.

Abstract

In severe coronavirus diseases 2019 (COVID-19), a high and potentially excessive use of antimicrobials for suspected bacterial co-infection and intensive care unit (ICU)-acquired infections has been repeatedly reported. To compare an ICU cohort of community-acquired pneumonia (CAP) with a cohort of severe COVID-19 pertaining to co-infections, ICU-acquired infections and associated antimicrobial consumption. We retrospectively compared a cohort of CAP patients with a cohort of COVID-19 patients matched according to organ failure, ICU length of stay (LOS) and ventilation days. Patient data such as demographics, infection focus, probability and severity, ICU severity scores and ICU and in-hospital mortality, days of antimicrobial therapy (DOT) and number of antimicrobial prescriptions, using an incremental scale, were registered and analysed. The total number of cultures (sputum, urinary, blood cultures) was collected and corrected for ICU LOS. CAP patients (n = 148) were matched to COVID-19 patients (n = 74). Significantly less sputum cultures (68.2% versus 18.9%, P < 0.05) and bronchoalveolar lavages (BAL) (73.7% versus 36.5%, P < 0.05) were performed in COVID-19 patients. Six (8.1%) COVID-19 patients were diagnosed with a co-infection. Respectively, 58 of 148 (39.2%) CAP and 38 of 74 (51.4%) COVID-19 patients (P = 0.09) developed ICU-acquired infections. Antimicrobial distribution, both in the number of prescriptions and DOT, was similar in both cohorts. We found a low rate of microbiologically confirmed bacterial co-infection and a high rate of ICU-acquired infections in COVID-19 patients. Infection probabilities, antimicrobial prescriptions and DOT were comparable with a matched CAP cohort.

Published
2021
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44. Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome

Author

Gentner, B, Tucci, F, Galimberti, S, Fumagalli, F, De Pellegrin, M, Silvani, P, Camesasca, C, Pontesilli, S, Darin, S, Ciotti, F, Sarzana, M, Consiglieri, G, Filisetti, C, Forni, G, Passerini, L, Tomasoni, D, Cesana, D, Calabria, A, Spinozzi, G, Cicalese, M, Calbi, V, Migliavacca, M, Barzaghi, F, Ferrua, F, Gallo, V, Miglietta, S, Zonari, E, Cheruku, P, Forni, C, Facchini, M, Corti, A, Gabaldo, M, Zancan, S, Gasperini, S, Rovelli, A, Boelens, J, Jones, S, Wynn, R, Baldoli, C, Montini, E, Gregori, S, Ciceri, F, Valsecchi, M, la Marca, G, Parini, R, Naldini, L, Aiuti, A, Bernardo, M, Gentner, Bernhard, Tucci, Francesca, Galimberti, Stefania, Fumagalli, Francesca, De Pellegrin, Maurizio, Silvani, Paolo, Camesasca, Chiara, Pontesilli, Silvia, Darin, Silvia, Ciotti, Francesca, Sarzana, Marina, Consiglieri, Giulia, Filisetti, Chiara, Forni, Giulia, Passerini, Laura, Tomasoni, Daniela, Cesana, Daniela, Calabria, Andrea, Spinozzi, Giulio, Cicalese, Maria-Pia, Calbi, Valeria, Migliavacca, Maddalena, Barzaghi, Federica, Ferrua, Francesca, Gallo, Vera, Miglietta, Simona, Zonari, Erika, Cheruku, Patali S, Forni, Claudia, Facchini, Marcella, Corti, Ambra, Gabaldo, Michela, Zancan, Stefano, Gasperini, Serena, Rovelli, Attilio, Boelens, Jaap-Jan, Jones, Simon A, Wynn, Robert, Baldoli, Cristina, Montini, Eugenio, Gregori, Silvia, Ciceri, Fabio, Valsecchi, Maria G, la Marca, Giancarlo, Parini, Rossella, Naldini, Luigi, Aiuti, Alessandro, Bernardo, Maria-Ester, Gentner, B, Tucci, F, Galimberti, S, Fumagalli, F, De Pellegrin, M, Silvani, P, Camesasca, C, Pontesilli, S, Darin, S, Ciotti, F, Sarzana, M, Consiglieri, G, Filisetti, C, Forni, G, Passerini, L, Tomasoni, D, Cesana, D, Calabria, A, Spinozzi, G, Cicalese, M, Calbi, V, Migliavacca, M, Barzaghi, F, Ferrua, F, Gallo, V, Miglietta, S, Zonari, E, Cheruku, P, Forni, C, Facchini, M, Corti, A, Gabaldo, M, Zancan, S, Gasperini, S, Rovelli, A, Boelens, J, Jones, S, Wynn, R, Baldoli, C, Montini, E, Gregori, S, Ciceri, F, Valsecchi, M, la Marca, G, Parini, R, Naldini, L, Aiuti, A, Bernardo, M, Gentner, Bernhard, Tucci, Francesca, Galimberti, Stefania, Fumagalli, Francesca, De Pellegrin, Maurizio, Silvani, Paolo, Camesasca, Chiara, Pontesilli, Silvia, Darin, Silvia, Ciotti, Francesca, Sarzana, Marina, Consiglieri, Giulia, Filisetti, Chiara, Forni, Giulia, Passerini, Laura, Tomasoni, Daniela, Cesana, Daniela, Calabria, Andrea, Spinozzi, Giulio, Cicalese, Maria-Pia, Calbi, Valeria, Migliavacca, Maddalena, Barzaghi, Federica, Ferrua, Francesca, Gallo, Vera, Miglietta, Simona, Zonari, Erika, Cheruku, Patali S, Forni, Claudia, Facchini, Marcella, Corti, Ambra, Gabaldo, Michela, Zancan, Stefano, Gasperini, Serena, Rovelli, Attilio, Boelens, Jaap-Jan, Jones, Simon A, Wynn, Robert, Baldoli, Cristina, Montini, Eugenio, Gregori, Silvia, Ciceri, Fabio, Valsecchi, Maria G, la Marca, Giancarlo, Parini, Rossella, Naldini, Luigi, Aiuti, Alessandro, and Bernardo, Maria-Ester

Abstract

Background Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. Methods We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an alpha-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. Results We now report interim results. The children's mean (+/- SD) age at the time of HSPC gene therapy was 1.9 +/- 0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced

Published
2021

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