CRISPR-Cas9 Modified Stem Cells for Sickle Cell Disease

Recruiting at 6 trial locations

Overseen By Medical Information

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Vertex Pharmaceuticals Incorporated

Must be taking: Hydroxyurea

Disqualifiers: HLA-matched donor, Prior HSCT, Infections, 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: Unknown

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 severe SCD and hydroxyurea (HU) failure or intolerance. 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. However, since the study involves participants with hydroxyurea failure or intolerance, it might be assumed that hydroxyurea is not required during the trial.

What data supports the effectiveness of the treatment CTX001, exa-cel for sickle cell disease?

Research shows that using CRISPR-Cas9 to edit stem cells can effectively correct the genetic mutation causing sickle cell disease. Studies have demonstrated that this approach can increase healthy hemoglobin levels and reduce sickle hemoglobin, potentially leading to clinical benefits for patients. ^{1 2 3 4 5}

Is the CRISPR-Cas9 treatment for sickle cell disease safe for humans?

Preclinical studies show that CRISPR-Cas9 gene editing for sickle cell disease appears safe, with no evidence of abnormal blood cell development, cancer risk, or other toxic effects in animal models. ^{1 2 3 5 6}

How is the treatment CTX001 for sickle cell disease different from other treatments?

CTX001 is unique because it uses CRISPR-Cas9 technology to edit the patient's own stem cells, correcting the genetic mutation that causes sickle cell disease. This approach aims to provide a long-lasting solution by directly addressing the root cause of the disease, unlike traditional treatments that mainly manage symptoms. ^{1 2 4 5 7}

Eligibility Criteria

This trial is for children with severe Sickle Cell Disease who have had at least two serious pain episodes a year and haven't responded well to or can't tolerate Hydroxyurea treatment. They should be suitable for their own stem cell transplant, not have had one before, and not currently have any major infections.

Inclusion Criteria

I have been diagnosed with severe sickle cell disease.

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

I've had two or more severe pain crises a year for the last two years.

Exclusion Criteria

I do not have any active serious infections.

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

I have had a stem cell transplant before.

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

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• CTX001

Trial Overview The study tests CTX001, which involves editing the patient's stem cells using CRISPR-Cas9 technology to treat severe SCD. It's an open-label trial meaning everyone knows they're getting this single-dose experimental therapy.

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

A new therapeutic approach combining lentiviral gene addition and CRISPR-Cas9 strategies shows promise for treating sickle cell disease (SCD) by allowing for effective gene editing and expression of anti-sickling hemoglobins with lower vector copy numbers.

This method not only enhances the levels of beneficial hemoglobins but also reduces the risk of genotoxicity associated with high vector amounts, making it a safer option for patients with SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. Ramadier, S., Chalumeau, A., Felix, T., et al.[2023]

A CRISPR-Cas9 gene correction strategy demonstrated up to 60% correction of the sickle cell disease-causing mutation in patient-derived hematopoietic stem cells, showing promising efficacy for potential treatment.

Preclinical studies in mice showed that the corrected cells engrafted successfully without signs of abnormal blood cell formation or tumor development, indicating a favorable safety profile for this gene therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. Lattanzi, A., Camarena, J., Lahiri, P., et al.[2022]

The study developed a non-integrating lentiviral system for delivering CRISPR-Cas9 components, which allows for safer and more efficient gene editing in hematopoietic stem cells without the toxicity associated with electroporation.

Using this new delivery method, researchers achieved a significant correction of the sickle cell disease mutation in the βs-globin gene, with up to 42% efficiency at the protein level, indicating a promising advancement in gene therapy for hereditary diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cas9 protein delivery non-integrating lentiviral vectors for gene correction in sickle cell disease. Uchida, N., Drysdale, CM., Nassehi, T., et al.[2021]

A novel hybrid reprogramming vector was developed to efficiently generate patient-specific induced pluripotent stem cells (iPSCs) from sickle cell disease (SCD) patients, achieving high efficiency without off-target modifications.

Using CRISPR/Cas9, the sickle cell mutation was corrected in these iPSCs with a correction efficiency of up to 67.9%, and whole-genome sequencing confirmed the absence of unintended genetic changes, indicating a safe approach for potential gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel HDAd/EBV Reprogramming Vector and Highly Efficient Ad/CRISPR-Cas Sickle Cell Disease Gene Correction. Li, C., Ding, L., Sun, CW., et al.[2018]

The study demonstrates that using a ribonucleoprotein (RNP) complex with Cas9 and single-stranded DNA oligonucleotide can effectively edit the genes of hematopoietic stem/progenitor cells (HSPCs) from sickle cell disease (SCD) patients, leading to reduced sickle hemoglobin and increased normal hemoglobin production.

Ex vivo edited HSPCs maintained the genetic corrections for at least 16 weeks in immunocompromised mice, indicating the potential for long-term therapeutic benefits in treating SCD and similar blood disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. DeWitt, MA., Magis, W., Bray, NL., et al.[2021]

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]

Using CRISPR-Cas9 to edit the LRF-binding site in hematopoietic stem/progenitor cells can increase fetal γ-globin production, which helps correct the sickling of red blood cells in sickle cell disease (SCD).

The study demonstrated high editing efficiency in repopulating stem cells, suggesting that targeting the LRF-binding site could be a promising approach for developing genome-editing therapies for SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Weber, L., Frati, G., Felix, T., et al.[2022]

References

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

Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. [2023]

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

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. [2022]

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

Cas9 protein delivery non-integrating lentiviral vectors for gene correction in sickle cell disease. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Novel HDAd/EBV Reprogramming Vector and Highly Efficient Ad/CRISPR-Cas Sickle Cell Disease Gene Correction. [2018]

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

Selection-free genome editing of the sickle mutation in human adult hematopoietic stem/progenitor cells. [2021]

6. 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]

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

Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. [2022]