CRISPR-Cas9 Modified Stem Cells for Sickle Cell Disease

Recruiting at 12 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment using CRISPR-Cas9 technology to modify stem cells for individuals with severe sickle cell disease (SCD). The goal is to determine if this treatment, known as CTX001 or exa-cel, can improve symptoms for those who haven't found success with hydroxyurea, a common SCD medication. Participants will receive a single infusion of these modified stem cells to assess safety and effectiveness. Candidates may be suitable for this trial if they have experienced at least two severe pain crises each year for the past two years and have not benefited from hydroxyurea treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering access to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that CTX001 is likely to be safe for humans?

Research has shown that CTX001, a treatment using specially modified stem cells, has promising safety results. In one study, patients with severe sickle cell disease (SCD) who received CTX001 did not experience any serious side effects for up to 48 months. Another report noted that many patients no longer needed blood transfusions after the treatment, indicating its safety.

The FDA has approved CTX001 for treating severe SCD in people aged 12 and older, further supporting its safety. While no treatment is completely without risk, current evidence suggests CTX001 is generally well-tolerated. However, discussing any potential side effects with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sickle cell disease?

CTX001 is unique because it uses CRISPR-Cas9 gene editing to modify a patient's own stem cells, offering a personalized approach to treating sickle cell disease. Unlike traditional treatments like hydroxyurea or regular blood transfusions, CTX001 targets the genetic root of the disease by editing the BCL11A gene, which plays a role in hemoglobin production. Researchers are excited about this treatment because it aims to provide a long-term solution by potentially curing the disease at the genetic level, reducing the need for ongoing treatment.

What evidence suggests that CTX001 might be an effective treatment for sickle cell disease?

Research has shown that CTX001, a treatment using specially modified stem cells, yields promising results for sickle cell disease (SCD). In studies, all patients treated with CTX001 avoided painful episodes, known as vaso-occlusive crises (VOCs), for at least a year. Early data also indicated an increase in healthy hemoglobin levels in the blood, suggesting that the treatment helps the body produce better-functioning red blood cells. Overall, the evidence indicates that CTX001 effectively treats severe cases of SCD. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03745287

A Safety and Efficacy Study Evaluating CTX001 in Subjects ... This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects with severe sickle cell disease (SCD). The study will evaluate the ...

2. ashpublications.org ashpublications.org/ashclinicalnews/news/8012/Full-Results-of-Exa-Cel-Study-Show-Continued

Full Results of Exa-Cel Study Show Continued Safety, Efficacy ... The study met both its primary and secondary endpoints: of the 30 evaluable patients, 97% were free from VOCs for at least 12 consecutive months, and 100% were ...

3. ir.crisprtx.com ir.crisprtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-present-new-data-22-patients

Press Release Beta thalassemia: All 15 patients were transfusion independent after CTX001 infusion - - Sickle cell disease: All seven patients were free of vaso-occlusive ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10112499/

5612617 EFFICACY AND SAFETY OF A SINGLE DOSE ... Exa-cel infusion led to elimination of transfusions in almost all patients with TDT and elimination of VOCs in all patients with SCD.

5. library.ehaweb.org library.ehaweb.org/eha/2021/eha2021-virtual-congress/325494/stephan.grupp.ctx001.for.sickle.cell.disease.safety.and.efficacy.results.from.html

CTX001 FOR SICKLE CELL DISEASE: SAFETY AND ... Early data from patients with SCD infused with CTX001 showed increased levels of total hemoglobin (Hb), HbF, and F-cell pancellularity over time ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38661449/

Exagamglogene Autotemcel for Severe Sickle Cell Disease Results: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets ...

7. crisprtx.com crisprtx.com/about-us/press-releases-and-presentations/crispr-therapeutics-and-vertex-announce-positive-safety-and-efficacy-data-from-first-two-patients-treated-with-investigational-crispr-cas9-gene-editing-therapy-ctx001-for-severe-hemoglobinopathies

CRISPR Therapeutics and Vertex Announce… One patient with severe sickle cell disease (SCD) received CTX001 in mid-2019 and data for this patient reflect four months of safety and efficacy follow-up.