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

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.

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 \