Gene-modified stem cell therapy for children with autosomal recessive osteopetrosis

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.