Assessing the Safety, Tolerability, and Efficacy of APR-2020 in Pediatric and Adolescent Subjects With RPS19 Deficient Diamond-Blackfan Anemia

Brief summary The goal of this clinical trial is to learn if APR-2020 is safe and can help treat Diamond-Blackfan Anemia (DBA) in adolescents and children. The main questions it aims to answer are: * Is APR-2020 safe and well tolerated? * Does APR-2020 modify or correct an underlying genetic condition which causes DBA? * Does APR-2020 reduce or eliminate the need for blood transfusions and/or restore certain blood counts affected by DBA? Participants will: * Take the drug one time as an infusion. * Undergo two rounds of a cellular harvest procedure in which their own cells will be used in the manufacturing of their own participant-specific product. * Initially return to the clinic for two years of follow up at increasingly sparse intervals.

This open-label, single-arm study evaluates the safety and efficacy of APR-2020 in transfusion-dependent, steroid-resistant pediatric and adolescent patients with RPS19-deficient Diamond-Blackfan Anemia (DBA). Disease Background: DBA is a congenital bone marrow (BM) failure syndrome characterized by early-onset hypoplastic anemia secondary to selective erythroid aplasia. The cardinal hematologic manifestation is a severe normochromic, macrocytic anemia in the presence of preserved leukocyte and platelet counts. In approximately 90% of affected individuals, hematologic abnormalities manifest within the first year of life; the median age at clinical presentation is approximately 2 months, with a median age at diagnosis of 3 months (Sieff 2023). Genotype-phenotype data have demonstrated substantial clinical heterogeneity both within and across molecular subtypes. Accordingly, the term DBA syndrome has been adopted to reflect the broader phenotypic spectrum, encompassing classic DBA-estimated to occur at an incidence of 5 to 10 per million live births with no significant sex predilection-as well as non-classical or attenuated presentations. Most patients exhibit a reticulocytopenic (hyporegenerative) anemia, consistent with impaired erythroid progenitor differentiation and maturation, with or without associated congenital anomalies or growth abnormalities (Vlachos et al. 2018). DBA is primarily caused by heterozygous pathogenic variants in genes encoding ribosomal proteins (RPs), resulting in ribosomal haploinsufficiency and defective ribosome biogenesis. The most frequently implicated genes include RPS19 (25-30%), RPL5 (7-12%), RPS26 (6-9%), RPL11 (5-7%), RPS24 (2-3%), and RPS10 (1-3%). Additional RP gene variants have been identified at lower frequencies (Sieff 2023; Wlodarski et al. 2024). RPS19 remains the most commonly mutated gene in DBA (Da Costa et al. 2020; Sieff 2023; Wlodarski et al. 2024). Rare pathogenic variants in non-ribosomal protein genes associated with DBA-like phenotypes-such as GATA1, TSR2, and EPO-have also been described but collectively account for fewer than 1% of cases (Da Costa et al. 2020; Wlodarski et al. 2024). Patients eligible for inclusion in the present study have a confirmed diagnosis of DBA attributable to pathogenic variants in RPS19. Study Population: The protocol will enroll 4 subjects with genetically confirmed RPS19-deficient DBA who demonstrate transfusion-dependent, corticosteroid-refractory disease. Study Drug: The study drug, APR-2020 is a gene therapy that consists of autologous cluster of differentiation (CD)34+ hematopoietic stem and progenitor cells (HSPCs) derived from mobilized peripheral blood (PB) from subjects with RPS19-deficient DBA. These CD34+ cells will be exposed ex-vivo to the Sponsor's highly purified and concentrated third generation self-inactivating (SIN) lentiviral vector (LVV), which provides the functioning RPS19 gene. The efficacy of APR-2020 was demonstrated through a rescu Покажи пълното описание...

Key Inclusion Criteria: 1. Confirmed diagnosis of RPS19-deficient DBA. 2. Signed informed consent by the subject or legally authorized representative. 3. Bone marrow analysis demonstrating normal cytogenetics except for RPS19-deficient DBA. 4. Subjects are between 2 and 18 years of age, inclusive. 5. Eligible for allogeneic marrow or stem cell transplant for DBA (non-critical cardiac and hepatic iron overload). 6. Corticosteroid resistance 7. Transfusion-dependent anemia 8. Willingness to return for long-term follow-up 9. Adequate renal and pulmonary function 10. Able to undergo hematopoietic stem cell transplant (HSCT) mobilization and apheresis procedures. Key Exclusion Criteria: 1. Availability of a suitable, consenting HLA-identical sibling donor. 2. Positive viral serology. 3. Clinically significant, active bacterial, viral, or fungal infection. 4. Any prior or current malignancy, myeloproliferative disorder, or myelodysplastic syndrome, except where therapy was curative excision (ie, in situ squamous cell carcinoma). 5. Any concerning molecular or cytogenetic abnormalities in hematopoietic cells. 6. Previous receipt of an allogeneic transplant or gene therapy. 7. Immediate family member with a known or suspected Familial Cancer Syndrome (including, but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers, excluding DBA). 8. Diagnosis of significant psychiatric disorder that could impact the subject's ability to participate in the study, in the opinion of the Investigator. 9. History of complex allo-immunization, as determined by the Investigator. 10. Women who are lactating/breast feeding or who plan to breastfeed within 6 months following APR-2020 infusion. 11. Men and females of childbearing potential who are unwilling to practice highly effective methods of birth control through the duration of the study. 12. Females with a positive serum pregnancy test at Screening or who are planning to become pregnant during the study period. 13. Liver disease, as evidenced by critical iron overload with magnetic resonance imaging (MRI) 14. Heart disease or Type 1 diabetes. 15. Evidence of significant pulmonary hypertension, per Investigator assessment. 16. Any other condition that would render the subject ineligible for HSCT, as determined by Investigator. 17. Contraindication to stem cell or bone marrow aspiration, mobilization or collection including allergies to filgrastim or plerixafor. 18. Currently enrolled in another investigational drug study or received an investigational study drug or procedure within 90 days of study enrollment. 19. A physical or emotional status that would prevent giving informed consent, protocol compliance, or adequate follow-up. 20. An assessment by the Investigator that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol. 21. Taking prohibited medications.