Gene-Modified Stem Cell Therapy for Children With Autosomal Recessive Osteopetrosis (ARO) (ARO)

A Phase I/II Open Label Study to Assess Safety, Feasibility and Efficacy of ex Vivo Expanded, Autologous Haematopoietic Stem and Progenitor Cell Populations That Contain CD34+ Cells Transduced With a Lentiviral Vector Encoding the TCIRG1 cDNA in Children With Autosomal Recessive Osteopetrosis Caused by Mutations in the TCIRG1 Gene.

This is a non-randomized, one-arm, open label, single-center, phase I/II, prospective study, to assess safety, feasibility and efficacy of FT024 in 8 children (Age: ≥ 28 days and ≤ 2 years old, Body weight: ≥ 4 kg) affected by ARO-1.

Once written informed consent has been obtained, and subsequently screening procedures have been completed, harvesting of HSPCs will occur. FT024 manufacturing will occur within a designated GMP manufacturing facility. Following FT024 release, patients will be admitted to the clinical center for the receipt of a reduced toxicity conditioning regimen based on Treosulfan and Thiotepa and then, the infusion of the FT024. Thereafter, regular follow-up of patients will occur for up to 2 years (+720 days).

In case of partial hematological recovery, additional FT024 boost will be administered without conditioning within + 180 days post first FT024 infusion. At the +720-day visit, patients will be invited to participate in a long-term follow-up study, which will last for an additional 13 years.

Patient recruitment is expected to take 3 years. The study will last approximately 5 years and 6 months, from the first visit of the first patient to the final visit of the last patient. Each patient will take part in the study for about 30 months, from screening to last follow up visit.

Study Overview

• Status: Recruiting
• Conditions: Osteopetrosis
• Intervention / Treatment: Genetic: FT024

Detailed Description

This phase I/IIa clinical trial is a non-randomized, open label, single-centre, therapeutic-exploratory, prospective study, to assess safety and efficacy of FT024 in up to 8 children affected by ARO aged ≤2 years of age and will be carried out at the Pediatric Clinical Research Unit/Pediatric Immuno-haematology and Bone Marrow Transplantation Unit, IRCCS Ospedale San Raffaele, Milan, Italy.

Once written informed consent has been obtained and subsequently screening procedures have been completed, harvesting of HSPCs will occur.

In cases of strong suspicion of osteopetrosis without a confirmed genetic diagnosis, and when the patient is unable to visit the clinical center for this inclusion criteria analysis due to their clinical condition, a preliminary remote evaluation for gene mutation analysis may be considered. In this case, remote signing of genetic analysis consent will be required before any evaluation and a blood sample will be sent to the laboratory in Milan, where the analysis will be performed. Blood sample will be collected at a local health care provider (HCP) or local healthcare facility or by home nursing.

If the diagnosis of TCIRG1-associated ARO is confirmed, patients who initially underwent genetic analysis remotely may proceed to Ospedale San Raffaele to complete the screening assessments. In such case, before undergoing any further screening procedures, the patient or parent/legal guardian will be asked to sign the main informed consent for participation in the clinical study. After completing the screening assessments and confirming eligibility, harvesting of HSPCs by leukapheresis or serial blood withdrawal will occur after mobilization and then sent to GMP facility to ATMP manufacturing.

Following ATMP release, patients will be admitted to hospital for receipt of a reduced toxicity conditioning regimen based on Treosulfan and Thiotepa, and infusion of the ATMP. In-patient monitoring will occur until haematological recovery occurred. Thereafter, regular follow-up of patients will take place until 2 years (+720 days). In case of logistical issues or patient's needs, remote visits can be performed. Within the first 180 days, the patient may be re-admitted to hospital for infusion of 1 or 2 ATMP boost doses if the criteria for incomplete hematologic recovery are fulfilled.

At the end of the study (+720 days), patients will be invited to continue long-term follow-up (up to 15 years after gene therapy administration), as required by the authorities (Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products. January 2018, EMEA/149995/2008 rev.1, Committee for Medicinal Products for Human Use [CHMP]). Additional written informed consent will be obtained to participate in this long-term follow-up study.

Recruitment of the planned 8 patients is expected to take around 3 years. The study will last approximately 5 years and 6 months, from the first visit of the first patient to the final visit of the last patient. Each patient will take part in the study for about 30 months, from screening to last follow up visit. A total of 10 visits (minimum) will be required including assessments, day hospital visits and in-patient hospitalization(s).

• Study Type: Interventional
• Enrollment (Estimated): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Francesca Tucci, Principal Incestigator; Phone Number: +390226439057; Email: tucci.francesca@hsr.it

Study Locations

• Italy
  • Italy
    • Milan, Italy, Italy, 20132
      • Recruiting
      • Ospedale San Raffaele
      • Contact: Francesca Tucci, Principal Investigator; Phone Number: +39 02 26439057; Email: tucci.francesca@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of autosomal recessive osteopetrosis caused by mutations in the TCIRG1 gene, defined by one of the following:

   1. Clinical features of osteopetrosis and documented pathogenic/likely pathogenic biallelic variants (homozygosity or compound heterozygosity, whereby at least 1 allele must contain a known pathogenic mutation) in the TCIRG1 gene causing malignant infantile osteopetrosis.
   2. If a patient presents with clinical features suggestive of severe osteopetrosis (i.e. generalized osteosclerosis, club-shaped long bones, skull base sclerosis, recurrent fractures and osteomyelitis, cranial nerve entrapment leading to visual and/or hearing loss, bone marrow insufficiency) and at least one pathogenic/likely pathogenic mutation of the TCIRG1 gene, the patient is eligible following discussion with an expert in this pathology.
2. Patient's parents/legal guardians' capacity to understand the study goals, the study requirements (i.e., attending study visits, completing questionnaires, taking study medications), potential risks associated with joining a study, and willingness to provide verbal and written informed consent.
3. Age: ≥ 28 days and ≤ 2 years old.
4. Body weight: ≥ 4 kg.

5. Adequate cardiac, pulmonary, renal and hepatic function as evidenced by:

   1. Left ventricular ejection fraction (LVEF) ≥45% by echo and normal electrocardiogram (ECG) or presence of abnormalities not significant for cardiac disease. Absence of clinically significant heart valve disease.
   2. Pulse oximetry ≥90% in room air and no evidence for parenchymal lung disease on chest X-ray or CT scan.
   3. serum creatinine <1.5x upper limit normal in the absence of any form of renal replacement therapy.
   4. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5 x and total bilirubin ≤1.5x upper limit of normal (ULN). Normal coagulation tests (INR <1.5).

Exclusion Criteria:

1. Availability of a medically appropriate, logistically feasible, fully HLA-matched (10/10) sibling or unrelated donor. The chances of finding a suitable, fully matched unrelated donor should be estimated through a preliminary donor bank search by an experienced transplant team. If the patient is judged unlikely to be treated with a fully matched allogeneic HSCT within 6 weeks from activating search procedures, he/she can be considered eligible for this gene therapy study.

   This criterion will not be applied to patients whose country of origin does not offer an allogeneic HSCT as a treatment option.

2. History of uncontrolled seizures or severe psychiatric symptoms.
3. Clinically relevant active viral, bacterial or fungal infection.
4. Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or active infection for Treponema Pallidum or Mycoplasma.
5. Known hypersensitivity to the drugs required for conditioning chemotherapy, or any excipients used in these products.
6. Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if long-acting agents).
7. Previous allogeneic HSCT or gene therapy with a different product.
8. Patients affected by neoplasia, a familial predisposition to hematologic malignancies or any hematologic/cytogenetic alterations that may suggest a high risk of developing hematologic malignancies.
9. Patients with end-organ damage or any other severe condition which, in the judgment of the investigator, would make the patient inappropriate for either HSPC collection or autologous transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label study with ex vivo expanded FT024 drug product; The dose range for ex vivo-expanded FT024 is as follows: target dose: 100-200x106 CD34+ cells/kg body weight;; minimum dose: 50x106 CD34+ cells/kg body weight;; maximum dose: 300x106 CD34+ cells/kg body weight; The route of administration will be intravenous infusion.	Genetic: FT024; Autologous haematopoietic stem and progenitor cell population containing CD34+ cells transduced with a lentiviral vector encoding the TCIRG1 cDNA and expanded ex vivo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival following the first FT024 infusion.	12 months and 24 months
Percentage of Participants Achieving Long-Term Engraftment Without Severe Cytopenias, Regular Red Blood Cell Transfusions, or Rescue Treatment.	Long-term engraftment of TCIRG1 LVV-Transduced Cells is defined as vector copy number (VCN) >0.2 in total blood or myeloid cells at 12 months after the first FT024 infusion. The endpoint is the percentage of participants who have no neutropenia or thrombocytopenia greater than Grade 3 and no regular red blood cell transfusion requirement compared with baseline, in the absence of rescue treatment (allogeneic transplantation with or without autologous back-up infusion).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants for Whom the Minimum Number of Autologous HSPCs Can Be Collected for Manufacturing	Percentage of patients for whom at least the minimum number of autologous HSPC (>10x106 CD34+ cells/kg) can be obtained. The cumulative amount of CD34+ cells that has been collected during one or several apheresis and/or blood withdrawal sessions, will be calculated and referred to the patient weight at the time of the last HSPC harvest.	Baseline
Frequency and Severity of Adverse Events and Serious Adverse Events	Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) attributed to procedures related to hematopoietic stem cell harvesting, conditioning regimen, or ATMP administration.	From Baseline up to Month 24.
Incidence of Malignancy or Abnormal Clonal Proliferation	Absence of malignancy or abnormal clonal proliferation assessed at 6, 12, and 24 months after first ATMP infusion. Evaluation includes clinical assessment, hematology and biochemistry tests, flow cytometry for lymphocyte subpopulations, vector copy number analysis, and bone marrow examination when clinically indicated. Additional investigations, including cytogenetic and molecular analyses, may be performed in case of suspected clonal expansion.	6, 12, and 24 months
Disability-Free Survival	Disability-free survival defined as absence of Grade ≥3 neutropenia or thrombocytopenia, no requirement for chronic blood product transfusion, no osteomyelitis, no requirement for major neurosurgery, and no pathologic bone fractures during the preceding 12 months.	Baseline and 24 months
Time to achieve hematologic recovery from the first ATMP infusion	Hematologic recovery is defined as the first of 3 consecutive days with neutrophil count (ANC) >0.5x109/L and platelets >20x109/L, maintained for at least 7 days in the absence of transfusions and/or growth factor support.	From Day 0 up to Month 24
Percentage of Participants for Whom a Manufactured FT024 Product Meets Release Specifications	Percentage of patients for whom a FT024 product conforming to specifications was manufactured and released to allow administration of minimum dose.	From Baseline to Day 6
Incidence of Replication Competent Lentivirus	Absence of replication competent lentivirus (RCL) assessed at 1, 6, 12, and 24 months after first ATMP infusion.	Baseline and 1, 6, 12 and 24 months
Percentage of patients who do not require a rescue treatment	Percentage of participants requiring rescue treatment including autologous back-up infusion and/or allogeneic hematopoietic stem cell transplantation.	12 months
Assessment of haematological parameters indicative of haematological reconstitution	Neutrophils and platelets levels will be measured as surrogate of haematological reconstitution at different time points. Modification of these levels correlates with effective haematological recovery.	1, 2, 3, 6, 9, 12, 18 and 24 months
Red Blood Cell and Platelet Transfusion Requirement	Change in monthly red blood cell and platelet transfusion requirements compared with the 30 days prior to first ATMP infusion.	Baseline and 1, 2, 3, 6, 12, 18 and 24 months
Effect of Boost Infusion on Hematologic Recovery	Change in neutrophil and platelet counts and transfusion requirements before and after boost infusion.	Pre-boost and +30-60 days and +80-120 days post-boost
Engraftment of genetically corrected cells	Longitudinal analysis of vector copy number in leukocyte populations from blood and/or bone marrow.	1, 2, 3, 6, 9, 12, 18 and 24 months
Long-Term Engraftment of TCIRG1 LVV-Transduced Cells	Percentage of participants with vector copy number >0.2 in total blood or myeloid cells at 12 months, without Grade ≥3 cytopenias, without regular red blood cell transfusion requirement, and without rescue treatment, stratified by number of boost infusions.	12 months
Health-Related Quality of Life	Assessed using PedsQL 4.0 Generic Core, PedsQL Infant Scales, and Stem Cell Transplant Module parent-proxy reports.	Baseline, 12 months and 24 months

Collaborators and Investigators

• Sponsor: Fondazione Telethon
• Collaborators: Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Estimated): June 20, 2026
• Primary Completion (Estimated): June 20, 2030
• Study Completion (Estimated): June 30, 2031

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 18, 2026
• First Posted (Actual): June 24, 2026

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 18, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: autosomal recessive osteopetrosis caused by the mutations in TCRG1 gene
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Osteosclerosis; Osteochondrodysplasias; Bone Diseases, Developmental; Osteopetrosis
• Other Study ID Numbers: ARO-FT024-01; 2024-518972-30-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No