Gene Therapy for Sickle Cell Anemia

Overseen By Emily Morris

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Daniel Bauer

Disqualifiers: Uncontrolled infection, Active malignancy, Major surgery, others

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

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

Trial Summary

What is the purpose of this trial?

A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine that uses genetic material (mostly DNA) from the patient to treat his or her own disease. In gene therapy, the investigators introduce new genetic material in order to fix or replace a diseased gene, with the goal of curing the disease. The procedure is similar to a bone marrow transplant, in that the patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but it is different because instead of using a different person's (donor) blood stem cells for the transplant, the patient's own blood stem cells are given back after the new genetic material has been introduced into those cells. This approach has the advantage of eliminating any risk of Graft-Versus-Host Disease (GVHD), reducing the risk of graft rejection, and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure. The method used to fix or replace a diseased gene is called gene editing. A person's own cells are edited using a specialized biological medicine that has been formulated for use in human beings. Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. Investigators have recently discovered a gene called BCL11A that is very important in the control of fetal hemoglobin expression. Increasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood, and therefore potentially cure the condition.

Will I have to stop taking my current medications?

The trial protocol specifies that if you are taking hydroxyurea, you should stop it when transfusions prior to gene therapy begin. For other medications, the protocol does not specify, so it's best to discuss with the trial team.

What data supports the effectiveness of the treatment Hematopoietic Stem Cell BCL11A Enhancer Gene Editing for Sickle Cell Anemia?

Research shows that editing the BCL11A enhancer in stem cells can increase fetal hemoglobin levels, which helps reduce the effects of sickle cell disease. Studies in animals and lab settings have demonstrated that these edited cells can persist for a long time and function well without harmful side effects. ^{1 2 3 4 5}

Is gene therapy for sickle cell anemia safe for humans?

Research shows that gene editing targeting the BCL11A enhancer in stem cells can persist without detectable toxicity in animal models, and similar approaches have shown no increased risk of harmful effects in preclinical studies. These findings suggest that the treatment is generally safe, but more human trials are needed to confirm this. ^{1 2 4 5 6}

How is the treatment Hematopoietic Stem Cell BCL11A Enhancer Gene Editing unique for sickle cell anemia?

This treatment is unique because it involves editing a specific part of a gene (BCL11A enhancer) in stem cells to increase fetal hemoglobin, which can prevent the sickling of red blood cells without causing harmful side effects. Unlike other treatments, it targets the genetic cause of the disease and has shown long-term effectiveness in maintaining healthy blood cells. ^{2 4 5 7 8}

Eligibility Criteria

This trial is for individuals with severe beta-thalassemia or sickle cell disease. Candidates must have a specific genetic variant (rs114518452). They should be eligible for bone marrow transplant but will use their own modified cells to avoid complications like GVHD.

Inclusion Criteria

I am between 13 and 40 years old.

My condition is considered severe by my doctor.

I have been diagnosed with sickle cell or β-thalassemia through genetic testing.

Exclusion Criteria

I have not had major surgery in the last 30 days.

I cannot take busulfan due to health reasons.

Specific findings on screening bone marrow aspirate/biopsy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Patients with SCD receive blood transfusions for 3 months prior to stem cell collection

12 weeks

Stem Cell Collection and Gene Editing

Peripheral stem cell mobilization and collection by apheresis, followed by gene editing

2-4 weeks

Conditioning and Infusion

Myeloablative conditioning with busulfan followed by infusion of gene-edited cells

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Hematopoietic Stem Cell BCL11A Enhancer Gene Editing

Trial Overview The trial tests gene editing on the patient's own blood stem cells, aiming to increase fetal hemoglobin production which could cure the disease. It involves modifying genes using Cas9 and then reintroducing these cells after chemotherapy.

Participant Groups

Group I: Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Daniel Bauer

Lead Sponsor

Trials

1

Recruited

10+

Findings from Research

A novel gene-editing approach using electroporation achieved significant correction of the sickle cell mutation in hematopoietic stem cells, with about 30% correction at the DNA level and 80% at the protein level, demonstrating its potential efficacy for treating sickle cell disease.

The study showed that gene-edited CD34+ cells could successfully engraft and function in both mouse models and rhesus macaques for up to 12 months, indicating the long-term viability of this gene correction strategy for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease locus in xenograft mouse and non-human primate models. Uchida, N., Li, L., Nassehi, T., et al.[2022]

Targeted genome editing using CRISPR/Cas9 and TALENs can successfully correct the sickle cell mutation in the β-globin gene in hematopoietic stem cells, leading to the production of normal hemoglobin.

In laboratory tests, over 18% of CD34+ cells showed successful gene modification, indicating the potential for effective treatment of sickle cell disease in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ cells. Hoban, MD., Lumaquin, D., Kuo, CY., et al.[2022]

Combining CRISPR-Cas9 editing of the BCL11A enhancers significantly enhances fetal hemoglobin (HbF) induction, which is crucial for treating β-hemoglobinopathies like sickle cell disease, as shown in patient-derived xenografts.

Editing hematopoietic stem and progenitor cells (HSPCs) without prior cytokine culture reduces the risk of unintended genetic damage while maintaining effective gene editing, suggesting a safer approach for potential in vivo therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. Zeng, J., Nguyen, MA., Liu, P., et al.[2023]

The BCH-BB694 lentiviral vector effectively reactivates fetal hemoglobin production while reducing harmful adult sickle hemoglobin in sickle cell disease, showing a 3- to 5-fold increase in fetal hemoglobin levels in transduced cells.

Preclinical studies indicate that BCH-BB694 is non-toxic and can be produced at a clinically relevant scale, supporting its potential for safe and effective use in human trials for treating sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Brendel, C., Negre, O., Rothe, M., et al.[2020]

References

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

Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease locus in xenograft mouse and non-human primate models. [2022]

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

Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone-Marrow-Derived CD34+ Hematopoietic Stem and Progenitor Cells. [2020]

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

CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ cells. [2022]

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

BCL11A enhancer-edited hematopoietic stem cells persist in rhesus monkeys without toxicity. [2021]

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

Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. [2023]

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

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. [2020]

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

Disruption of the BCL11A Erythroid Enhancer Reactivates Fetal Hemoglobin in Erythroid Cells of Patients with β-Thalassemia Major. [2020]

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

Strict in vivo specificity of the Bcl11a erythroid enhancer. [2021]