A Trial to Evaluate Safety and Efficacy of RP-L401-0120 in Subjects With Infantile Malignant Osteopetrosis

A Phase I Clinical Trial for Gene Therapy in Infantile Malignant Osteopetrosis (IMO) to Evaluate the Safety and Preliminary Efficacy of Autologous CD34+ Enriched Cells Transduced With a LV Vector Encoding the TCIRG1 Gene

The primary objective of this Phase 1 study is to evaluate the therapeutic safety and feasibility of the investigational product (IP), RP-L401.

This is a non-randomized Phase 1 study to evaluate the preliminary safety and efficacy of hematopoietic gene therapy consisting of autologous CD34+ enriched hematopoietic cells transduced with the lentiviral vector (LV) carrying the human TCIRG1 transgene (RP-L401) in pediatric patients with IMO. Following myeloablative conditioning patients will receive an infusion of the genetically modified hematopoietic stem and progenitor cells (HSPCs).

Inclusion Criteria:

1. A confirmed diagnosis of IMO with documented TCIRG1 mutation.
2. Age at least 1 month with minimum weight of 4 kg
3. Absence of debilitating hydrocephalus (defined as hydrocephalus at NCI CTCAE v5.0 Grade 3 or higher persisting despite shunt or similar procedural intervention).
4. Lansky Play Scale of at least 60%
5. Preserved hepatic function (AST/ALT ≤3.0 ULN; bilirubin ≤1.5 ULN; to minimize potential for excessive toxicity from busulfan conditioning)
6. No concomitant medical or other conditions that would represent a contraindication to autologous hematopoietic stem cell transplant.
7. Absolute neutrophil count of ≥500/mm3 and platelet count of ≥25,000/mm3
8. No prior allogeneic or other hematopoietic stem cell transplant.
9. Availability of a non-autologous rescue (back-up) hematopoietic stem cell donor/source

Exclusion Criteria:

1. Availability of medically-feasible HLA-matched sibling donor for allogeneic HSCT.

2. Any medical or other contraindication for either apheresis or autologous transplant as determined by the Investigator.

3. Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed.

4. Active hematologic or solid organ malignancy, not including non-melanoma skin cancer or another carcinoma in situ.

5. Uncontrolled seizure disorder.

6. Renal dysfunction as defined by a glomerular filtration rate <30 mL/min/1.73m2 or dialysis dependence.

7. Serious infections with persistent bloodstream pathogens at time of trial entry

8. Pulmonary dysfunction as defined by either:

   • Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection) or
   • Oxygen saturation (by pulse oximetry) <90% resulting from pulmonary conditions (intermittent hypoxia secondary to IMO-related choanal atresia will not be considered exclusionary)