Safety and Efficacy Evaluation of γ-globin Reactivated Autologous Hematopoietic Stem Cells

Study Overview
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Brief Summary
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This is a non-randomized, open label, single-dose, phase 1/2 study in up to 12 participants with β-thalassemia major.This study aims to evaluate the safety and efficacy of the treatment with γ-globin reactivated autologous hematopoietic stem cells in subjects with β-thalassemia major.

Detailed Description
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γ-globin reactivated autologous hematopoietic stem cells will be manufactured using Crispr/Cas9 gene editing system. Subject participation for this study will be 1 year. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for up to 15 years post-transplant.

Official Title
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an Open Label Trial of Evaluation of the Safety and Efficacy of Treatment With γ-globin Reactivated Autologous Hematopoietic Stem Cells in Subjects With β-thalassemia Major

Conditions
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β Thalassemia Major

Intervention / Treatment
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* Biological: γ-globin reactivated autologous hematopoietic stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fully understand and voluntarily sign informed consent. 5-15years old. At least one legal guardian and/or Subjects to sign informed consent. Clinically diagnosed as β-thalassemia major, phenotypes including β0β0, β+β0,βEβ0 genotype. Subjects with no affection with EBV, HIV, CMV, TP, HAV, HBV and HCV. Subjects body condition eligible for autologous stem cell transplant. Exclusion Criteria: Subjects acceptable for allogeneic hematopoietic stem cell transplantation and have an available fully matched related donor. Active bacterial, viral, or fungal infection. Treated with erythropoietin prior 3 months. Immediate family member with any known hematological tumor. Subjects with severe psychiatric disorders to be unable to cooperate. Recently diagnosed as malaria. History of complex autoimmune disease. Persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value >3 X the upper limit of normal (ULN). Subjects with severe heart, lung and kidney diseases. With serious iron overload, serum ferritin>5000mg/ml. Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician or Investigator. Subjects who are receiving treatment from another clinical study, or have received another gene therapy. Subjects or guardians had resisted the guidance of the attending doctor. Subjects whom the investigators do not consider appropriate for participating in this clinical study.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: γ-globin reactivated autologous hematopoietic stem cells<br>each subject will accept one dose of γ-globin reactivated autologous hematopoietic stem cells | Biological: γ-globin reactivated autologous hematopoietic stem cells<br>* gene edited autologous hematopoietic stem cells with γ-globin expression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation of γ-globin reactivated autologous hematopoietic stem cells | Proportion of subjects with engraftment; Overall survival. | up to 24 months post transplant | 
| Incidence and severity of adverse events as a measure of safety and tolerability. Adverse events assessed according to NCI-CTCAE v5.0 criteria | Incidence of AEs and SAEs post transplant | up to 24 months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy evaluation of γ-globin reactivated autologous hematopoietic stem cells | Proportion of subjects achieving transfusion independence for at least 6 months (TI6); Proportion of subjects achieving TI12; Proportion of alleles with intended genetic modification in bone marrow cells; Change in total hemoglobin concentration; Change from baseline in annualized frequency and volume of packed RBC transfusions. | up to 24 months post transplant |