Gene Therapy for Beta Thalassemia

Overseen By Jaladhikumar Patel

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Malignancy, HIV, Hepatitis, Cardiac dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment ALS20, CHOP-ALS20 for beta thalassemia?

Research shows that the ALS20 treatment can produce high levels of hemoglobin (a protein in red blood cells that carries oxygen) with fewer copies of the gene inserted into cells, which may reduce potential side effects. This has been confirmed in studies with cells from sickle cell disease patients and in animal models, suggesting it could be effective for beta thalassemia as well. ^{1 2 3 4 5}

Is gene therapy for beta thalassemia safe for humans?

Gene therapy using ALS20 for beta thalassemia has shown promising safety results in studies, with low risk of harmful effects on the genome and successful long-term outcomes in experiments. However, there are concerns about the risk of blood-related cancers and the high cost of treatment, which have affected its availability. ^{1 5 6 7 8}

What is the purpose of this trial?

The main goal of this study is to find out if the blood disorder called transfusion-dependent beta thalassemia can be safely treated by modifying blood stem cells. This is done by collecting blood stem cells from the subject, modifying those cells, adding a healthy beta globin gene, and then giving them back to the subject. It is hoped that these modified cells will decrease the need for blood transfusions. The gene modified blood stem cells are called CHOP-ALS20 ("study drug"). This experimental gene therapy has not been tried on human beings before and is not FDA approved.

Research Team

Janet Kwiatkowski, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for individuals with transfusion-dependent beta thalassemia, a blood disorder. Participants must have a history of needing regular blood transfusions. Specific eligibility criteria are not provided, but typically include factors like age range, overall health status, and the severity of the condition.

Inclusion Criteria

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

I have beta thalassemia and need regular blood transfusions.

My thalassemia diagnosis is confirmed through genetic testing.

Exclusion Criteria

Diffusion capacity of carbon monoxide (DLco) <50% of predicted (corrected for Hb)

I have a family member who is a match for a bone marrow transplant.

Pulse oximetry in room air <92%

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo myeloablative conditioning with busulfan

1-2 weeks

Treatment

Infusion of autologous hematopoietic stem and progenitor cells transduced with the novel lentiviral vector ALS20

1 day

1 visit (in-patient)

Engraftment

Monitoring for neutrophil and platelet engraftment

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• ALS20

Trial Overview The study is testing an experimental gene therapy called CHOP-ALS20 (study drug) to treat beta thalassemia by modifying patients' own blood stem cells with a healthy beta globin gene and returning them to the patient's body.

Participant Groups

Group I: beta thalassemia Experimental Treatment 1 Intervention

This arm will evaluate the safety and efficacy of infusing autologous hematopoietic stem and progenitor cells (HSPC) transduced with the novel lentiviral vector ALS20 that encodes the human βA-T87Q-globin gene, following myeloablative conditioning with busulfan.

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Findings from Research

The ALS20 construct for gene therapy has been shown to produce significantly higher levels of adult hemoglobin compared to other constructs, indicating its potential efficacy in treating beta-globinopathies.

ALS20 may allow for effective treatment with less than two copies integrated per genome, which could reduce the risk of genome toxicity and the need for intensive myeloablation, enhancing the safety of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lentiviral vector ALS20 yields high hemoglobin levels with low genomic integrations for treatment of beta-globinopathies. Breda, L., Ghiaccio, V., Tanaka, N., et al.[2022]

Gene therapy using lentiviral vectors has shown promise as a curative approach for β-thalassemia, with the first successful clinical trial conducted in France demonstrating significant disease improvement.

Advancements in vector design and methods for monitoring gene integration are paving the way for safer and more effective clinical trials in the future, addressing limitations of current treatments like blood transfusions and bone marrow transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards more successful gene therapy clinical trials for β-thalassemia. Drakopoulou, E., Papanikolaou, E., Georgomanoli, M., et al.[2022]

Gene therapy for β-thalassemia has made significant progress, with ongoing clinical trials focusing on gene augmentation and novel approaches like genome editing and transgene-mediated activation of γ-globin.

Future studies may shift towards using induced pluripotent stem cells as targets for gene therapy, building on insights gained from current research and clinical trials involving human erythropoietic stem cells from β-thalassemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent trends in the gene therapy of β-thalassemia. Finotti, A., Breda, L., Lederer, CW., et al.[2020]

Gene therapy offers a promising approach to treat beta-thalassemia by transferring normal β-globin or γ-globin genes into a patient's own hematopoietic stem cells, potentially allowing for the production of normal red blood cells.

While allogeneic bone marrow transplants can cure beta-thalassemia, they are limited to patients with matched donors; gene therapy could provide a more accessible treatment option, though challenges remain in optimizing gene transfer and ensuring safety during clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic therapy for beta-thalassemia: from the bench to the bedside. Arumugam, P., Malik, P.[2022]

Gene therapy approaches, including the use of lentiviral vectors and CRISPR-Cas9 technology, have shown promising results in achieving transfusion independence for many patients with transfusion-dependent thalassemia (TDT), with follow-up data spanning multiple years.

Despite the effectiveness of these gene therapies, challenges such as the risk of secondary hematological malignancies and high treatment costs are hindering access and commercialization, even after conditional approval in Europe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia. Thuret, I., Ruggeri, A., Angelucci, E., et al.[2022]

The study presents a novel gene therapy approach for beta-thalassemia, targeting patients who do not have a matched donor for bone marrow transplantation, which is currently the only curative option.

This gene therapy involves using autologous CD34+ hematopoietic cells and aims to safely deliver a regulated beta-globin gene, with extensive biosafety testing and a reduced intensity conditioning regimen to minimize patient risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for homozygous beta-thalassemia. Is it a reality? Boulad, F., Rivière, I., Sadelain, M.[2012]

Using a combination of single-strand oligodeoxynucleotides and high-fidelity CRISPR/Cas9, researchers achieved a highly efficient and seamless correction of the β-thalassemia mutation in patient-specific induced pluripotent stem cells (iPSCs).

The corrected iPSCs showed minimal off-target effects and expressed normal β-globin transcripts when differentiated into hematopoietic progenitor cells, indicating a safe and effective approach for potential cell therapy in treating β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection. Liu, Y., Yang, Y., Kang, X., et al.[2020]

CRISPR/Cas9 gene editing technology shows promise as a curative treatment for β-thalassemia by enabling precise genome editing, which can help patients avoid complications associated with traditional treatments like graft-versus-host disease (GVHD) and graft rejection.

Current clinical trials are focusing on strategies to reactivate γ-globin and increase fetal hemoglobin production in hematopoietic stem cells, highlighting the potential of CRISPR-based therapies to address the underlying genetic causes of β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia. Zeng, S., Lei, S., Qu, C., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Lentiviral vector ALS20 yields high hemoglobin levels with low genomic integrations for treatment of beta-globinopathies. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Towards more successful gene therapy clinical trials for β-thalassemia. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Recent trends in the gene therapy of β-thalassemia. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Genetic therapy for beta-thalassemia: from the bench to the bedside. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Gene therapy for homozygous beta-thalassemia. Is it a reality? [2012]

7. United States pubmed.ncbi.nlm.nih.gov

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection. [2020]

8. Germany pubmed.ncbi.nlm.nih.gov

CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia. [2023]