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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy, ALS20 (also known as CHOP-ALS20), which could assist individuals with transfusion-dependent beta thalassemia, a blood disorder requiring regular transfusions. Researchers aim to determine if altering blood stem cells to include a healthy gene can reduce the need for transfusions. The treatment involves extracting the patient's stem cells, modifying them, and returning them to the body. Individuals who have frequently received blood transfusions due to beta thalassemia may be suitable candidates for this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's function in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative therapy.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that ALS20, the gene therapy under study for beta thalassemia, produced promising results in lab studies. Tests on mice with beta thalassemia indicated that ALS20 could effectively treat the condition with fewer than one copy of the gene per cell. However, this treatment has not yet been tested on humans and lacks FDA approval.

As this trial is in its early stages, information on how well people tolerate ALS20 remains limited. Earlier trials with similar gene therapies have focused on safety and found them to be well-tolerated. However, each therapy differs, so more information is needed for ALS20. Participants should be aware that this treatment is experimental and discuss potential risks with their healthcare providers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for beta thalassemia, which often involve regular blood transfusions or bone marrow transplants, ALS20 works differently by using gene therapy. Researchers are excited about ALS20 because it uses autologous hematopoietic stem and progenitor cells (HSPC) that are genetically modified with a lentiviral vector to introduce the human βA-T87Q-globin gene. This innovative approach aims to correct the underlying genetic defect of beta thalassemia, potentially reducing or eliminating the need for ongoing blood transfusions. By targeting the root cause of the disease, ALS20 could offer a more sustainable and long-term solution for patients.

What evidence suggests that this gene therapy might be an effective treatment for beta thalassemia?

Research has shown that the ALS20 gene therapy, which participants in this trial will receive, aims to help people with beta thalassemia by adding a healthy gene to their blood stem cells. This new gene, called beta globin, could reduce the need for regular blood transfusions. Early studies indicate that the ALS20 method can lead to high levels of hemoglobin, which is crucial for carrying oxygen in the blood. The treatment modifies the patient’s own stem cells and then returns them to the person. Although this approach is new, the underlying science suggests it could be a promising way to manage beta thalassemia. ^{1 2 3 4 6}

Who Is on the Research Team?

Janet Kwiatkowski, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. research.chop.edu research.chop.edu/chop-als20-lentiviral-gene-therapy-for-beta-thalassemia

CHOP-ALS20 Lentiviral gene Therapy for Beta Thalassemia This clinical trial aims to test a new gene therapy in adults (18 to 35 years old) with beta thalassemia who require regular red cell transfusions.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06364774

ALS20-101 Lentiviral Gene Therapy for Beta Thalassemia 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 ...

3. chop.edu chop.edu/research-studies/chop-als20-lentiviral-gene-therapy-beta-thalassemia

CHOP-ALS20 Lentiviral gene Therapy for Beta Thalassemia This clinical trial aims to test a new gene therapy in adults (18 to 35 years old) with beta thalassemia who require regular red cell transfusions.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8058492/

Lentiviral vector ALS20 yields high hemoglobin levels with ... Successful treatment of beta-globinopathies with ALS20 could potentially be achieved at less than two copies per genome, minimizing the risk of ...

5. trialx.com trialx.com/clinical-trials/listings/319842/als20-101-lentiviral-gene-therapy-for-beta-thalassemia/

ALS20-101 Lentiviral Gene Therapy for Beta Thalassemia The main goal of this study is to find out if the blood disorder called transfusion-dependent beta thalassemia can be safely treated by ...

6. ctsearchsupport.org ctsearchsupport.org/clinical-trials/als20-101-lentiviral-gene-therapy-for-beta-thalassemia

Gene therapy (ALS20) using your own cells to treat ... To find out if gene therapy, ALS20, is safe and works well to treat transfusion-dependent beta thalassemia.