Gene therapy for treating beta thalassemia

Phase 1/2 Study Evaluating the Safety and Efficacy of Gene Therapy Employing Lentiviral Vector ALS20-transduced Hematopoietic Progenitor Cells in Subjects With Transfusion-dependent-thalassemia

This study is testing a new gene therapy that uses patients' own modified blood cells to see if it can help young adults with beta thalassemia need fewer blood transfusions.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 18 Years to 40 Years
• Sex: All
• Sponsor: Children's Hospital of Philadelphia (Academic / other)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT06364774 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the safety and efficacy of a novel gene therapy for transfusion-dependent beta thalassemia by modifying patients' own blood stem cells. Blood stem cells will be collected from participants, genetically modified to include a healthy beta globin gene using a lentiviral vector, and then reinfused into the patients. The study will involve up to 12 subjects aged 18 to 35 years and will assess whether this treatment can reduce the need for blood transfusions. This is a pioneering approach, as the gene therapy has not been previously tested in humans.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 18 to 35 with transfusion-dependent beta thalassemia and specific genetic profiles.

Not a fit: Patients with non-transfusion-dependent beta thalassemia or those outside the specified age range may not benefit from this study.

Why it matters

Potential benefit: If successful, this therapy could significantly reduce or eliminate the need for regular blood transfusions in patients with beta thalassemia.

How similar studies have performed: While gene therapy approaches for beta thalassemia are emerging, this specific method using the ALS20 vector is novel and has not been tested in humans before.

Eligibility criteria

Inclusion Criteria:

1. Age 18 to \< 40 years at the time of consent
2. Diagnosis of transfusion dependent beta thalassemia (β0 β0, β+β0, β+β+, βEβ0, βEβ+,β0 or β+ /βA + alpha triplication(s)). Transfusion-dependent is defined as a history of receiving at least 120 mL/kg/year packed red blood cells or at least 8 transfusions per year in the past two years. The first 2 subjects enrolled must have a non- β0 β0 genotype.
3. Genetic confirmation of α and β thalassemia diagnosis (β0β0, β+β0, β+β+, βEβ0, βEβ+, β0 or β+ /βA + alpha triplication(s)) by a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory is required.
4. Clinically stable, Karnofsky score at least 70, and eligible to undergo Hematopoietic Stem Cell Transplantation (HSCT).
5. Female subjects of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 6 months after CHOP-ALS20 infusion
6. Male subjects of reproductive capacity must agree to use effective contraception from start of mobilization through at least 6 months after CHOP-ALS20 infusion
7. All potential treatment options including allogeneic HSCT (HLA-matched related, HLA-matched unrelated, and haploidentical) as well as FDA approved gene therapy options have been thoroughly discussed with the independent hematologist and/or transplant physician and subject agrees to proceed with this clinical trial.

Exclusion Criteria:

1. Prior receipt of HSCT or gene therapy
2. More than one alpha globin gene deletions/mutations.
3. Any prior or current malignancy (excluding adequately treated basal or squamous cell carcinoma of the skin)
4. Known cancer predisposition syndrome
5. Positive for HIV-1, HIV-2, Human T Cell Lymphotropic Virus-1,2 (HTLV-1, HTLV-2) or active hepatitis B or active hepatitis C infection
6. Clinically significant active bacterial, viral (including COVID-19 and influenza), fungal, or parasitic infection (temporary exclusion)
7. Clinically significant bleeding disorder
8. Evidence of cardiac dysfunction (left ventricular ejection fraction \<50% or shortening fraction \<27%) or clinically significant arrhythmia
9. Evidence of advanced liver disease (ALT \>5x the upper limit of normal (ULN), prothrombin time \>1.5 x ULN, direct bilirubin \> 3x ULN) not attributable to iron chelation therapy, or evidence of bridging fibrosis on liver biopsy or fibrosis stage of F3 or higher by magnetic resonance elastography (MRE) if obtained as part of clinical care
10. Liver R2 or R2 MRI or liver biopsy with liver iron concentration 15 mg/g dw (temporary exclusion)
11. Diffusion capacity of the lungs for carbon monoxide (DLco) \<50% of predicted (corrected for Hb)
12. Pulse oximetry in room air \<92%
13. Evidence of renal dysfunction (creatinine \>1.5x ULN or Glomerular Filtration Rate (GFR) \<70 ml/min/1.73 m2 based on cystatin C/creatinine equation)
14. Cardiac T2 MRI \< 10 ms
15. Platelet count \<100,000/mcL or absolute neutrophil count \<1000/mcL except if attributed to benign ethnic neutropenia
16. Unable to receive red cell transfusion (significant allo/auto immunization)
17. Uncontrolled systemic hypertension
18. Uncontrolled seizure disorder
19. Diagnosis of a significant psychiatric disorder that could seriously impede the ability to participate in the study as determined by the investigator
20. Immediate family member with a known or suspected Familial Cancer Syndrome
21. Contraindication to anesthesia
22. For female subjects, pregnancy or breastfeeding
23. Participation in another clinical trial of an investigational drug within 30 days or 5 drug half-lives, whichever is longer, of screening (temporary exclusion)
24. Any other condition that would render the subject ineligible for mobilization/apheresis and/or HSCT as determined by the investigator

Where this trial is running

Philadelphia, Pennsylvania

• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Janet Kwiatkowski, MD — Children's Hospital of Philadelphia
• Study coordinator: Janet Kwiatkowski, MD

Conditions Beta-Thalassemia; Thalassemia; Beta Thalassemia; gene therapy; beta globin gene