CRISPR Therapy (CTX001) for Thalassemia

Recruiting at 5 trial locations

Overseen By Medical Information

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Vertex Pharmaceuticals Incorporated

Disqualifiers: Prior HSCT, Sickle cell variant, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-dose, open-label study in pediatric participants with TDT. The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) (CTX001).

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 team or your doctor.

What data supports the effectiveness of the treatment CTX001 for Thalassemia?

Research shows that CRISPR gene editing, like in CTX001, can effectively correct genetic mutations causing beta-thalassemia, leading to restored normal blood function and reducing the need for blood transfusions. In clinical trials, patients treated with similar CRISPR-based therapies have shown increased fetal hemoglobin levels and achieved transfusion independence. ^{1 2 3 4 5}

Is CRISPR Therapy (CTX001) safe for humans?

Research on CRISPR therapy for thalassemia and sickle cell disease shows promising safety results. In studies, patients treated with CRISPR-edited cells did not show evidence of harmful off-target effects or tumor formation, suggesting the treatment is generally safe. ^{1 4 5 6 7}

How does the treatment CTX001 for thalassemia differ from other treatments?

CTX001 is unique because it uses CRISPR gene-editing technology to modify the patient's own stem cells, aiming to correct the genetic mutations causing thalassemia. This approach potentially offers a long-term solution by enabling the body to produce healthy blood cells, unlike traditional treatments that require regular blood transfusions and iron removal therapy. ^{1 3 4 8 9}

Eligibility Criteria

This trial is for children with Transfusion-Dependent β-Thalassemia (TDT) who need regular blood transfusions and are suitable for a stem cell transplant. They must have specific genetic forms of TDT confirmed by the study's lab. Those with a perfect match donor, previous transplants, certain sickle cell disease variants, or active infections can't participate.

Inclusion Criteria

I have needed regular blood transfusions for at least 6 months.

I have been diagnosed with Thalassemia and my condition is confirmed by genetic testing.

I am considered a good candidate for a stem cell transplant using my own cells.

Exclusion Criteria

I have had a stem cell transplant before.

I have the sickle cell β-thalassemia variant.

I have a healthy, fully matched donor for my treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of CTX001 through a central venous catheter

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• CTX001

Trial Overview The trial tests CTX001, which involves editing patients' own stem cells using CRISPR-Cas9 technology to potentially treat TDT. It's an open-label study where all participants receive one dose of the modified cells after a conditioning regimen.

Participant Groups

Group I: CTX001 Experimental Treatment 1 Intervention

CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive single infusion of CTX001 through central venous catheter.

CTX001 is already approved in European Union, United States for the following indications:

Approved in European Union as CTX001 for:

• Transfusion-dependent β-thalassemia (TDT)
• Severe sickle cell disease (SCD)

Approved in United States as CTX001 for:

• Transfusion-dependent β-thalassemia (TDT)
• Severe sickle cell disease (SCD)

Who Is Running the Clinical Trial?

Vertex Pharmaceuticals Incorporated

Lead Sponsor

Trials

267

Recruited

36,100+

Dr. David Altshuler

Vertex Pharmaceuticals Incorporated

Chief Medical Officer since 2020

MD, PhD

Dr. Reshma Kewalramani

Vertex Pharmaceuticals Incorporated

Chief Executive Officer since 2020

MD, trained in internal medicine and nephrology

CRISPR Therapeutics

Industry Sponsor

Trials

7

Recruited

630+

Findings from Research

The study demonstrates that targeting specific mutations in thalassemia, such as IVS1-110G>A and IVS2-654C>T, using advanced gene-editing techniques (Cas9 and Cas12a/Cpf1) in hematopoietic stem cells can effectively restore normal gene function.

This approach shows high efficiency in correcting mutations and reversing abnormal splicing in blood cells, suggesting it could significantly benefit patients with transfusion-dependent β-thalassemia by potentially reducing their need for transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. Xu, S., Luk, K., Yao, Q., et al.[2022]

A novel CRISPR/Cas9-based gene-editing strategy targeting the HBB gene for beta-thalassemia showed approximately 50% efficiency in co-transfecting CRISPR and donor template plasmids in HEK293 cells, with a subsequent HDR efficiency of about 37.5%.

The study successfully isolated HDR-positive cells using a combination of selection markers and negative selection methods, indicating that this approach could be a promising avenue for developing effective gene therapies for beta-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design Principles of a Novel Construct for HBB Gene-Editing and Investigation of Its Gene-Targeting Efficiency in HEK293 Cells. Lotfi, M., Ashouri, A., Mojarrad, M., et al.[2023]

The DARE (disruption of aberrant regulatory elements) technique effectively corrected β-globin expression in IVSI-110(G>A) β-thalassemia transgenic cells, showing potential for targeted repair of various disease-causing mutations.

This method demonstrated high efficiency and flexibility, suggesting it could be applied to at least 14 known thalassemia mutations and other inherited diseases, paving the way for personalized therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements. Patsali, P., Mussolino, C., Ladas, P., 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]

Using CRISPR-Cas9 to edit the BCL11A enhancer in CD34+ cells from two patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) resulted in over 80% successful gene modification without off-target effects.

Both patients showed significant clinical improvements, including high levels of fetal hemoglobin, transfusion independence, and elimination of vaso-occlusive episodes in the SCD patient, more than a year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. Frangoul, H., Altshuler, D., Cappellini, MD., et al.[2021]

CRISPR-Cas9 gene editing shows promise in correcting β-thalassemia mutations and enhancing the production of adult hemoglobin (HbA), which could significantly benefit patients with this hereditary disease.

The review suggests combining CRISPR-Cas9 gene editing with pharmacological methods to induce fetal hemoglobin (HbF) as a safer alternative to reduce potential genotoxicity associated with multiplex gene editing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from &#946;-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing. Finotti, A., Gambari, R.[2023]

CRISPR/Cas9 successfully corrected β-thalassemia mutations in patient-specific induced pluripotent stem cells (iPSCs), promoting the development of healthy hematopoietic stem cells (HSCs) in laboratory mice.

The corrected HSCs expressed normal β-globin (HBB) without causing tumors in various organs after implantation, indicating a safe and effective approach for personalized treatment of β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Combination of CRISPR/Cas9 and iPSC Technologies in the Gene Therapy of Human β-thalassemia in Mice. Ou, Z., Niu, X., He, W., et al.[2018]

A CRISPR/Cas9 genome-editing approach successfully targeted the HBG promoters to mimic a natural mutation that increases fetal hemoglobin (HbF) levels, showing promise for treating β-thalassemia.

In experiments with hematopoietic stem and progenitor cells from β0-thalassemia patients, a 20% editing efficiency led to a corresponding 20% increase in HbF, indicating the potential for this method to induce therapeutic levels of HbF across various β-thalassemia types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of therapeutic levels of HbF in genome-edited primary &#946;0 39-thalassaemia haematopoietic stem and progenitor cells. Mingoia, M., Caria, CA., Ye, L., et al.[2021]

A novel genome editing strategy using Cas9 and AAV6 successfully introduced natural mutations that increase γ-globin expression, which is beneficial for treating β-thalassemia, in both cell lines and primary cells from patients.

The edited hematopoietic stem and progenitor cells (HSPCs) not only showed increased γ-globin levels but also retained their ability to reconstitute blood cell production long-term in a mouse model, indicating potential for effective and lasting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Fetal Hemoglobin by Introducing Natural Hereditary Persistence of Fetal Hemoglobin Mutations in the γ-Globin Gene Promoters for Genome Editing Therapies for β-Thalassemia. Lu, D., Xu, Z., Peng, Z., et al.[2023]

References

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

Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Design Principles of a Novel Construct for HBB Gene-Editing and Investigation of Its Gene-Targeting Efficiency in HEK293 Cells. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements. [2020]

4. Germany pubmed.ncbi.nlm.nih.gov

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

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

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from &#946;-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing. [2023]

7. England pubmed.ncbi.nlm.nih.gov

The Combination of CRISPR/Cas9 and iPSC Technologies in the Gene Therapy of Human β-thalassemia in Mice. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Induction of therapeutic levels of HbF in genome-edited primary &#946;0 39-thalassaemia haematopoietic stem and progenitor cells. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Induction of Fetal Hemoglobin by Introducing Natural Hereditary Persistence of Fetal Hemoglobin Mutations in the γ-Globin Gene Promoters for Genome Editing Therapies for β-Thalassemia. [2023]