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| Name | Class |
|---|---|
| Fondazione Telethon | OTHER |
| Orchard Therapeutics | INDUSTRY |
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This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene for the treatment of patients affected by transfusion dependent beta-thalassemia
Both adults and pediatric patients will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow for patients < 8 years in case mobilization will not be feasible) and transduced with GLOBE lentiviral vector encoding for the human beta-globin gene.
This study will enroll 10 patients allocated in 3 groups, according to age and conditioning regimen:
Patients are included regardless of the beta globin gene mutation, provided an adequate cardiac, renal, hepatic and pulmonary function is demonstrated. Patients with severe iron overload are excluded as well as patients with active viral infections. Pediatric patients can be enrolled only in absence of a human leukocyte antigen (HLA)-identical sibling or a suitable 10/10 matched unrelated donor.
The treated patients will be followed for 2 years. After completion of the 2 years follow up, patients will be enrolled in a long term follow up study and followed up for at least other additional 6 years.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Adults | Experimental | ≥18 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously. |
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| Elderly children | Experimental | 8-17 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously. |
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| Younger children | Experimental | 3-7 years (4 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene | Genetic | Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10^6/Kg and a maximum dose of 20 x 10^6/Kg, depending on the yield of cells. The product will be injected intraosseously. |
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival | Number of patients alive all over the trial | 2 years |
| Achievement of hematological engraftment | Haematological engraftment is defined as first day of neutrophil count >500/mm3 and platelets >20,000/mm3 on 3 consecutive blood counts. | within day +60 after gene therapy |
| Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE |
| 0-24 months after gene therapy |
| Short-term safety and tolerability of the different conditioning regimens | The percentage of patients with the following clinical events from day -5 to +100 days from injection: NCI (National Cancer Institute Common Terminology Criteria grading) ≥2 and metabolic/laboratory NCI ≥3. | from day -5 (first day of conditioning treatment) to day 100 after gene therapy |
| Overall safety and tolerability measured by AE recording | The number of AEs (adverse events) and SAEs (serious adverse events) and the percentage of subjects experiencing AEs and SAEs in the 24 months post injection will be summarized by severity and within body system involved. | 0-24 months after gene therapy |
| Polyclonal engraftment |
| Measure | Description | Time Frame |
|---|---|---|
| Transfusion independence | Transfusion independence is defined as ≤ 1 transfusion in the previous 6 months | 9 months, 1, 1.5 and 2 years after gene therapy |
| Adequate haemoglobin level | Haemoglobin level will be assessed by full blood counts in patients achieving transfusion independence. Adequate haemoglobin is defined as haemoglobin >9 g/dl in adults and >10 g/dl in children. |
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Inclusion Criteria:
Written informed consent
Transfusion-dependent beta-thalassemia (any genotype). Transfusion dependence is defined as receiving ≥ 8 transfusions of blood per year over a minimum of 2 years.
Karnofsky Index or Lansky > 80%
Age ≥ 3 years and < 65 years
Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
Low risk thrombophilic screen and negative history of significant previous thrombotic events
For all patients in reproductive age, agreement to use highly effective and adequate method of contraception while receiving treatment phase and for at least 12 months following drugs administration (including both females of child bearing potential and males with partners of child bearing potential)
Good adherence to transfusion and chelation programme as indirect evidence of good adherence to treatment and follow-up evaluations for current trial
Availability of an adequate and well documented transfusion history (at least previous 6 months) or availability to follow a regular transfusion regimen according to guidelines and provide a detailed transfusion record of the 6 months prior to intervention phase
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alessandro Aiuti, MD, PhD | Ospedale San Raffaele | Principal Investigator |
| Fabio Ciceri, MD | Ospedale San Raffaele | Study Chair |
| Sarah Marktel, MD | Ospedale San Raffaele | Study Chair |
| Maria Domenica Cappellini, MD | IRCCS Policlinico Foundation | Study Chair |
| Giuliana Ferrari, PhD | Telethon Institute of Gene Therapy, Ospedale San Raffaele | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ospedale San Raffaele | Milan | 20132 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23845947 | Background | Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013 Aug 23;341(6148):1233151. doi: 10.1126/science.1233151. Epub 2013 Jul 11. | |
| 17671653 |
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| Type | Date | Date Unknown |
|---|---|---|
| Release | Jan 15, 2024 | |
| Reset | Jul 11, 2024 | |
| Release | Apr 29, 2026 | |
| Reset | May 20, 2026 |
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| Release Date | Unrelease Date | Unrelease Date Unknown | Reset Date | MCP Release Number |
|---|---|---|---|---|
| Jan 15, 2024 | Jul 11, 2024 | |||
| Apr 29, 2026 |
| ID | Term |
|---|---|
| D017086 | beta-Thalassemia |
| ID | Term |
|---|---|
| D013789 | Thalassemia |
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
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The percentage of subjects with polyclonality of haematopoiesis will be estimated at 6, 12, 18 and 24 months from injection. Polyclonality of haematopoiesis will be defined as > 1000 unique integration sites retrieved from peripheral blood and/or bone marrow cells. |
| From 6 months to 2 years after gene therapy |
| Reduction in transfusion frequency up to transfusion independence | Transfusions will be recorded as mLs of blood/kg/months | from -7 months before gene therapy to 2 years after gene therapy |
| 0-24 months after gene therapy |
| Adequate engraftment of genetically corrected cells | Engraftment will be assessed by vector-specific quantitative Polymerase Chain reaction (PCR) on bone marrow. Adequate engraftment is defined as ≥ 0.15 VCN/genome. (VCN = Vector Copy Number) | 6, 12, and 24 months after gene therapy |
| Transgene expression | Transgene expression will be evaluated by globin chains and/or hemoglobin synthesis on peripheral blood and/or bone marrow samples by HPLC and/or electrophoresis analysis | 6, 12, and 24 months after gene therapy |
| Improvement of health-related quality of life | Health-related quality of life will be assessed by the use of standardized questionnaires | 12 and 24 months |
| Background |
| Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, Urbinati F, Valacca C, Scaramuzza S, Aker M, Slavin S, Cazzola M, Sartori D, Ambrosi A, Di Serio C, Roncarolo MG, Mavilio F, Bordignon C. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007 Aug;117(8):2233-40. doi: 10.1172/JCI31666. |
| 19179314 | Background | Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58. doi: 10.1056/NEJMoa0805817. |
| 23845948 | Background | Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11. |
| 20979441 | Background | Frittoli MC, Biral E, Cappelli B, Zambelli M, Roncarolo MG, Ferrari G, Ciceri F, Marktel S. Bone marrow as a source of hematopoietic stem cells for human gene therapy of beta-thalassemia. Hum Gene Ther. 2011 Apr;22(4):507-13. doi: 10.1089/hum.2010.045. Epub 2011 Mar 4. |
| 18650378 | Background | Miccio A, Cesari R, Lotti F, Rossi C, Sanvito F, Ponzoni M, Routledge SJ, Chow CM, Antoniou MN, Ferrari G. In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10547-52. doi: 10.1073/pnas.0711666105. Epub 2008 Jul 23. |
| 16732270 | Background | Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi Sergi L, Benedicenti F, Ambrosi A, Di Serio C, Doglioni C, von Kalle C, Naldini L. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol. 2006 Jun;24(6):687-96. doi: 10.1038/nbt1216. Epub 2006 May 28. |
| 20665635 | Background | Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F, Mastropietro F, Amato A, Tonon G, Refaldi C, Cappellini MD, Andreani M, Lucarelli G, Roncarolo MG, Marktel S, Ferrari G. Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Mol Med. 2010 Aug;2(8):315-28. doi: 10.1002/emmm.201000083. |
| May 20, 2026 |
| Jul 1, 2026 |
| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |